Intraocular delivery devices and methods therefor

ABSTRACT

Injection devices for delivering pharmaceutical compositions into the eye are described. Some devices include a resistance component for controllably deploying an injection needle through the eye wall. The resistance component may be disposed on the injector device, or on a portion of the injection device housing, or on a drug reservoir. Some devices may be removably attached to a drug reservoir, for example, through a luer connector. Other devices may comprise internal luer seal for securely connecting a drug conduit of the device to the luer cavity of a drug reservoir. Yet other devices may comprise a priming-enabling element to facilitate the drug priming of a shielded needle. Related methods and systems comprising the devices are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. application Ser. No.13/841,144 filed Mar. 15, 2013, which claims priority to U.S.Provisional Application Ser. No. 61/619,308 filed Apr. 2, 2012, and U.S.Provisional Application Ser. No. 61/668,588 filed Jul. 6, 2012, thedisclosures of which are hereby incorporated by reference in theirentirety.

FIELD

Described here are devices that are configured to safely and accuratelydeliver pharmaceutical formulations into the eye. Specifically, thedevices may integrate various features that allow easy manipulation ofthe devices, and which may be beneficial for positioning of the deviceson the ocular surface. Some devices include features that filterpharmaceutical formulations injected into the eye. Systems and methodsfor intraocularly delivering the pharmaceutical formulations using thedevices are also described.

BACKGROUND

The eye is a complex organ comprised of many parts that enable theprocess of sight. Vision quality depends on the condition of eachindividual part and the ability of these parts to work together. Forexample, vision may be affected by conditions that affect the lens(e.g., cataracts), retina (e.g., CMV retinitis), or the macula (e.g.,macular degeneration). Topical and systemic drug formulations have beendeveloped to treat these and other ocular conditions, but each has itsdrawbacks. For example, topical therapies that are applied on thesurface of the eye typically possess short residence times due to tearflow that washes them out of the eye. Furthermore, delivery of drugsinto the eye is limited due to the natural barrier presented by thecornea and sclera, and additional structures if the intended targetresides within the posterior chamber. With respect to systemictreatments, high doses of drug are often required in order to obtaintherapeutic levels within the eye, which increases the risk of adverseside-effects.

Alternatively, intravitreal injections have been performed to locallydeliver pharmaceutical formulations into the eye. The use ofintravitreal injections has become more common due to the increasedavailability of anti-vascular endothelial growth factor agents for thetreatment of acute macular degeneration (AMD). Agents approved by theFDA for intravitreal injection to treat AMD include ranibizumab(Lucentis®: Genetech, South San Francisco, Calif.) and pegaptanib sodium(Macugen®: Eyetech Pharmaceuticals, New York, N.Y.). In addition,intravitreal bevacizumab (Avastin®: Genentech, South San Francisco,Calif.) has been widely used in an off-label application to treatchoroidal neovascularization. Increased interest in developing new drugsfor delivery directly into the vitreous for the treatment of macularedema, retinal vein occlusion, and vitreous hemorrhage also exists.

Currently, commercially available intravitreal injection devices lackmany features that are useful in exposing the site of injection,stabilizing the device against the sclera, and/or controlling the angleand depth of injection. Many of the devices described in the patentliterature, e.g., WO 2008/084064 and U.S. 2007/0005016, are also part ofmulti-component systems that are generally time consuming to set up anduse. The increased procedure time associated with these devices may inturn increase the risk of complications. Further, having to manipulatemany components by itself may increase the risk of complications due touser error. A serious complication of intraocular injection isintraocular infection, termed endophthalmitis that occurs due to theintroduction of pathogenic organisms such as bacteria from the ocularsurface into the intraocular environment, or trauma to the ocularsurface tissues such as corneal or conjunctival abrasion.

Accordingly, new devices for performing intravitreal injections would bedesirable. Ergonomic devices that simplify the injection procedure andreduce the risk of complications would be useful. Devices thataccurately and atraumatically inject drugs, e.g., liquid, semisolid, orsuspension-based drugs, into the eye would also be useful.

SUMMARY

Described here are devices, methods, and systems for deliveringpharmaceutical formulations into the eye. The devices may be integrated.By “integrated” it is meant that various features that may be beneficialin delivering the pharmaceutical formulations into the eye, e.g., in asafe, sterile, and accurate manner, are combined into a single device.For example, features that may aid appropriate placement on the desiredeye surface site, help position the device so that the intraocular spaceis accessed at the proper angle, help to keep the device tip stablewithout moving or sliding on the ocular surface once it has beenpositioned during the entire drug injection, adjust or controlintraocular pressure, and/or help to minimize trauma, e.g., from theforce of drug injection or contact or penetration of the eye wallitself, may be integrated into a single device. More specifically, theintegrated devices may be used in minimizing trauma due to directcontact with the target tissue or indirectly through force transmissionthrough another tissue or tissues such as the eye wall or vitreous gel,as well as minimizing trauma to the cornea, conjunctiva, episclera,sclera, and intraocular structures including, but not limited to, theretina, the choroid, the ciliary body, and the lens, as well as theblood vessels and nerves associated with these structures. Features thatmay be beneficial in reducing the risk of intraocular infectiousinflammation such as endophthalmitis and those that may reduce pain mayalso be included. It should be understood that the pharmaceuticalformulations may be delivered to any suitable target location within theeye, e.g., the anterior chamber or posterior chamber. Furthermore, thepharmaceutical formulations may include any suitable active agent andmay take any suitable form. For example, the pharmaceutical formulationsmay be a solid, semi-solid, liquid, etc. The pharmaceutical formulationsmay also be adapted for any suitable type of release. For example, theymay be adapted to release an active agent in an immediate release,controlled release, delayed release, sustained release, or bolus releasefashion.

In general, the devices described here include a housing sized andshaped for manipulation with one hand. The housing typically has aproximal end and a distal end, and an ocular contact surface at thehousing distal end. A conduit in its pre-deployed state will usuallyreside within the housing. The conduit will be at least partially withinthe housing in its deployed state. In some instances, the conduit isslidably attached to the housing. The conduit will generally have aproximal end, a distal end, and a lumen extending therethrough. Anactuation mechanism may be contained within the housing that is operablyconnected to the conduit and a reservoir for holding an active agent. Atrigger may also be coupled to the housing and configured to activatethe actuation mechanism. In one variation, a trigger is located on theside of the device housing in proximity to the device tip at the ocularcontact surface (the distance between the trigger and device tip rangingbetween 5 mm to 50 mm, between 10 mm to 25 mm, or between 15 mm to 20mm), so that the trigger can be easily activated by a fingertip whilethe device is positioned over the desired ocular surface site with thefingers of the same hand. In another variation, a trigger is located onthe side of the device housing at 90 degrees to a measuring component,so that when the device tip is placed on the eye surface perpendicularto the limbus, the trigger can be activated with the tip of the secondor third finger of the same hand that positions the device on the ocularsurface. In one variation, a measuring component is attached to theocular contact surface. In some variations, a drug loading mechanism isalso included.

The actuation mechanism may be manual, automated, or partiallyautomated. In one variation, the actuation mechanism is a spring-loadedactuation mechanism. Here the mechanism may include either a singlespring or two springs. In another variation, the actuation mechanism isa pneumatic actuation mechanism.

The application of pressure to the surface of the eye may beaccomplished and further refined by including a resistance component,e.g., a dynamic resistance component to the injection device. Thedynamic resistance component may include a slidable element coupled tothe housing. In some variations, the slidable element comprises adynamic sleeve configured to adjust the amount of pressure applied tothe eye surface. In other variations, the dynamic resistance componentis configured as an ocular wall tension control mechanism.

In one variation, the injection device includes a housing sized andshaped for manipulation with one hand, the housing having a proximal endand a distal end, a resistance band at least partially surrounding thehousing having a thickness between about 0.01 mm to about 5 mm, adynamic resistance component having proximal end and a distal end, anocular contact surface at the housing or device distal end; a conduit atleast partially within the housing, the conduit having a proximal end, adistal end, and a lumen extending therethrough, and an actuationmechanism coupled to the housing and operably connected to the conduitand a reservoir for holding an active agent.

In another variation, the injection device includes integratedcomponents and includes a housing sized and shaped for manipulation withone hand, the housing having a proximal end and a distal end, and asectoral measuring component coupled to a distal end of the housing ordevice. The sectoral measuring component may have a circumference orperiphery, or have a central (core) member having a proximal end, adistal end, and a circumference, and comprising a plurality of radiallyextending members. The injection device may also include a conduit atleast partially within the housing, the conduit having a proximal end, adistal end, and a lumen extending therethrough, an actuation mechanismcoupled to the housing and operably connected to the conduit and areservoir for holding an active agent, and a dynamic resistancecomponent.

In yet a further variation, the injection device may include a housingsized and shaped for manipulation with one hand, the housing having awall, a proximal end and a distal end, an ocular contact surface at thehousing or device distal end, a conduit at least partially within thehousing, the conduit having a proximal end, a distal end, and a lumenextending therethrough, an actuation mechanism coupled to the housingand operably connected to a reservoir for holding an agent, a dynamicresistance component, and a filter coupled to the device.

In some variations, the injector device for delivering a drug can beremovably attached to a drug reservoir, and may include a needleassembly, the needle assembly comprising a drug conduit; a measuringcomponent; and a priming-enabling component.

Described here are also systems for delivering compositions into theeye. The systems may include a housing sized and shaped for manipulationwith one hand, the housing having a proximal end and a distal end; andan ocular contact surface at the housing distal end. The conduit may atleast be partially disposed within the housing, and have a proximal end,a distal end, and a lumen extending therethrough. Typically a reservoiris disposed within the housing for holding the composition thatcomprises an active agent. Here the systems may also include a variableresistance component coupled to the housing distal end and an airremoval mechanism, where the air removal mechanism is configured toremove air from the composition before the composition is delivered intothe eye.

Alternatively, the systems for delivering a composition into the eye mayinclude a syringe body having a proximal end and a distal end, and areservoir for containing a composition therein, and an injectorattachment removably coupled to the distal end of the syringe comprisinga variable resistance component. The system may further include an airremoval mechanism disposed within the injector attachment, where the airremoval mechanism is configured to remove air from the compositionbefore the composition is delivered into the eye.

The systems described herein may further comprise a terminalsterilization mechanism and/or a jet control mechanism in addition to anair removal mechanism. The air removal mechanism may comprise ahydrophobic filter material having a pore size. The pore size may rangefrom about 0.05 μm to about 50 μm, from about 0.1 μm to about 10 μm, orfrom about 0.2 μm to about 5 μm. In some variations the air removalmechanism comprises a plurality of hydrophobic filters. The inclusion ofan air removal mechanism may be particularly beneficial when acomposition comprising ranibizumab or other viscous compositions areinjected into the eye.

The drug delivery systems may specifically be provided with an air orgas-resistance component (e.g., a hydrophilic filter) and a vent (e.g.,a hydrophobic filter). A hydrophilic filter membrane may increase theresistance to air or gas flow and prevent it from passing through a drugconduit while also diverting it through a hydrophobic filter vent andout of the device to facilitate air or gas removal from the drugcomposition. The vent and gas-resistance resistance components may beadjacent to each other. The vent and gas-resistance components may alsobe integrally formed with the drug conduit or needle hub, or provided asseparate, attachable/detachable components (with the needle hub or anypart of the injection device). The gas-resistance component may be atleast partially air-impermeable under any condition, or at leastpartially air-impermeable under certain conditions, e.g., when wetted.The gas-resistance component may prevent air in the drug compositionfrom entering a drug conduit. The vent may provide an anti-airlockmechanism, or a gas (air)-removal mechanism. For example, the vent maycomprise an air-release valve or a hydrophobic membrane.

In some variations, the systems for delivering a pharmaceuticalformulation into the eye include an injector device and a drugreservoir. Here the injector device can be removably attached to a drugreservoir, and may include a needle assembly, the needle assemblycomprising a drug conduit; a measuring component; and a priming-enablingcomponent. The pharmaceutical formulations may include an anti-VEGFagent selected from the group consisting of ranibizumab, bevacizumab,aflibercept, and modifications, derivatives, and analogs thereof, andcombinations thereof, as the active agent. In one variation, theadministration of ranibizumab or bevacizumab may be beneficial. In othervariations, the pharmaceutical formulation may include aflibercept,ocriplasmin, a steroid, a placenta-derived growth factor, aplatelet-derived growth factor, or combinations thereof, as the activeagent. In further variations, the active agent may comprise ananti-complement agent, an anti-complement fraction agent, acomplement-blocking agent, a complement-enhancing agent, a classiccomplement pathway inhibiting agent, an alternative complementinhibiting agent, a classic complement pathway potentiating agent, analternative complement potentiating agent, or a combination thereof.

In use, the devices deliver drug into the intraocular space bypositioning an ocular contact surface of the integrated device on thesurface of an eye, where the device further comprises a reservoir forholding an active agent and an actuation mechanism, and applyingpressure against the surface of the eye at a target injection site usingthe ocular contact surface, and then delivering an active agent from thereservoir into the eye by activating the actuation mechanism. The stepsof positioning, applying, and delivering are completed with one hand. Insome instances, a topical anesthetic is applied to the surface of theeye before placement of the device on the eye. An antiseptic may also beapplied to the surface of the eye before placement of the device on theeye.

The application of pressure against the surface of the eye using theocular contact surface may also generate an intraocular pressure rangingbetween 15 mm Hg to 120 mm Hg, between 20 mm Hg to 90 mm Hg, or between25 mm Hg to 60 mm Hg. As further described below, the generation ofintraocular pressure before deployment of the dispensing member(conduit) may reduce scleral pliability, which in turn may facilitatethe penetration of the conduit through the sclera, decrease unpleasantsensation associated with the conduit penetration through the eye wallduring an injection procedure and/or prevent backlash of the device.

The methods may also include placing an ocular contact surface of aninjection device against the eye wall, generating variable resistance toconduit advancement as the conduit is deployed through the eye wall,removing air from the composition before the composition is deliveredinto the eye by passing the composition through an air removalmechanism, and injecting the composition into the eye. The forcerequired to initiate movement against the generated resistance may beabout 5 gm to about 100 gm of force or about 10 gm to about 30 gm offorce. In some variations, it may take about 20 gm to about 25 gm offorce to initiate movement of the resistance component.

In some instances, the method may include coupling an injectorattachment to a syringe body, the injector attachment comprising avariable resistance component, an air removal mechanism, an ocularcontact surface, and a needle, and the syringe body having a proximalend and a distal end, and a reservoir for containing a compositiontherein; placing the ocular contact surface of the injector attachmentagainst the eye wall; generating variable resistance to needleadvancement as the needle is deployed through the eye wall; removing airfrom the composition before the composition is delivered into the eye bypassing the composition through the air removal mechanism; and injectingthe composition into the eye.

The drug delivery devices, components thereof, and/or various activeagents may be provided in systems or kits as separately packagedcomponents. The systems or kits may include one or more injectiondevices and/or injector attachments, as well as one or more activeagents. The devices may be preloaded or configured for manual drugloading. When a plurality of active agents is included, the same ordifferent active agents may be used. The same or different doses of theactive agent may be used as well. The systems or kits will generallyinclude instructions for use. They may also include anesthetic agentsand/or antiseptic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B depict front views of exemplary ocular contact surfaces.

FIGS. 2A-2C show side views of additional exemplary ocular contactsurfaces that include measuring components.

FIGS. 3A1-3A3 and FIGS. 3B1-3B3 show side views of other exemplaryocular contact surfaces.

FIG. 4A and FIGS. 4B1-4B2 depict perspective and front views of anexemplary flanged ocular contact surface.

FIGS. 5A1-5A2 and FIGS. 5B1-5B2 depict side and perspective views ofexemplary flat and convex ocular contact surfaces.

FIGS. 6A1-6A2 and FIGS. 6B1-6B2 show side and front views of exemplarysoft or semi-solid ocular contact surfaces.

FIGS. 7A1-7A2, FIGS. 7B1-7B2, FIGS. 7C1-7C2, and FIGS. 7D-7E showadditional exemplary ocular contact surfaces, including ocular contactsurfaces having a high-traction interface.

FIG. 8 illustrates how an exemplary measuring component works to retractthe eyelid and measure a certain distance from the limbus.

FIGS. 9A-9C show exemplary arrangements of measuring components aroundan ocular contact surface.

FIGS. 10A-10C depict other exemplary measuring components and how theywork to measure a certain distance from the limbus.

FIGS. 11A-11D show further exemplary measuring components.

FIG. 12 shows an exemplary device that includes a marking tip member.

FIG. 13 illustrates how marks made on the surface of the eye by anexemplary marking tip member can be used to position the device at atarget injection site.

FIGS. 14A-14C show perspective views of exemplary sharp conduits.

FIGS. 15A1-15A2 show side views of exemplary bevel angles.

FIGS. 16A-16D depict cross-sectional views of exemplary conduitgeometries.

FIG. 17 depicts a cross-sectional view of additional exemplary conduitgeometries.

FIGS. 18A-18C show side and cross-sectional views (taken along line A-A)of an exemplary flattened conduit.

FIG. 19 shows an exemplary mechanism for controlling exposure of theconduit.

FIG. 20 provides another exemplary conduit exposure control mechanism.

FIG. 21 shows an exemplary device having a front cover and back cover.

FIG. 22 illustrates how the device may be filled with a pharmaceuticalformulation using an exemplary drug loading member.

FIGS. 23A-23C depict other examples of drug loading members.

FIGS. 24A-24D show an exemplary fenestrated drug loading member.

FIGS. 25A-25B show an exemplary fenestrated drug loading memberinterfaced with a drug source.

FIGS. 26A-26C depicts a side, cross-sectional view of an exemplarytwo-spring actuation mechanism.

FIG. 27 is a side, cross-sectional view of another exemplary two-springactuation mechanism.

FIG. 28 depicts a perspective view of a device including a furtherexample of a two-spring actuation mechanism in its pre-activated state.

FIG. 29 is a cross-sectional view of the device and two-spring actuationmechanism shown in FIG. 28.

FIG. 30 is a cross-sectional view of the device shown in FIG. 28 afterthe two-spring actuation mechanism has been activated.

FIGS. 31A-31C illustrate how the trigger in FIG. 28 actuates the firstspring of the two-spring actuation mechanism to deploy the conduit.

FIGS. 32A-32C are expanded views that illustrate how release of thelocking pins in FIG. 28 work to activate the second spring of thetwo-spring actuation mechanism.

FIGS. 33A-33B depict the device of FIG. 28 with an exemplary loadingport.

FIG. 34 is a perspective view of an exemplary device with a pneumaticactuation mechanism.

FIGS. 35A-35B provide cross-sectional views of the device shown in FIG.34. FIG. 35A show the pneumatic actuation mechanism in a pre-activatedstate. FIG. 35B shows the pneumatic actuation mechanism after deploymentof the conduit.

FIG. 36 is a cross-sectional view of an exemplary device including asingle spring actuation mechanism.

FIG. 37 is a cross-sectional view of the device shown in FIG. 36 thatshowing the single spring actuation mechanism after deployment of theconduit.

FIG. 38 is a side, cross-sectional view of an exemplary drug-loadingpiston.

FIGS. 39A-39I depict various views of exemplary device tips.

FIG. 40 shows an exemplary device with a sliding cap.

FIGS. 41A-41B provide cross-sectional views of another exemplary devicehaving a two-spring actuation mechanism.

FIG. 42 depicts an enlarged sectional view an exemplary dynamic sleeve.

FIGS. 43A-43D illustrate an exemplary method of advancement of adispensing member and drug injection.

FIGS. 44A-44D depict exemplary positional indicator components.

FIGS. 45A-45J show various aspects of exemplary fine sleeve mobilitycontrol components.

FIG. 46 is a graphic depiction of the amount of resistance forcegenerated by a dynamic sleeve according to one variation.

FIG. 47 depicts an end view of an exemplary sectoral measuringcomponent.

FIG. 48 shows a perspective view of one variation of an intraocularinjection device.

FIGS. 49A and 49B are expanded views of the exemplary dynamic sleeveshown in FIG. 48. FIG. 49A depicts a side view of the sleeve. FIG. 49Bis a cross-sectional view of the sleeve shown in FIG. 49A taken alongline B-B.

FIG. 50 is an expanded end view of the sectoral measuring componentshown in FIG. 48.

FIG. 51 depicts a sectoral measuring component according to anothervariation on the surface of the eye at the corneo-scleral limbus.

FIGS. 52A-52C show an exemplary access (drug loading) port in theinjection device housing as well as an exemplary stopper for sealing aninjection device access port, and how the location of the stoppercorresponds with the location of an opening in a reservoir.

FIG. 53 depicts a partial cross-sectional view of an exemplary injectorattachment.

FIGS. 54A-54C show various views of another exemplary injectorattachment.

FIGS. 55A-G depict exemplary filter arrangements that include ahydrophilic filter and a hydrophobic filter.

FIG. 56 depicts a cross-sectional view of an exemplary needlestabilization or needle guide mechanism.

FIGS. 57A and 57B show another variation of an injector attachmenthaving a needle stabilization mechanism or needle guide mechanism.

FIGS. 58A-58C show an exemplary injection device. FIG. 58A is aperspective assembled view of the device, FIG. 58B is a side view of thedevice in FIG. 58A with components shown in more detail, and FIG. 58C isan expanded view of the domed actuator shown in FIGS. 58B and 58C.

FIG. 59 is a graph that depicts an exemplary resistance profile.

FIG. 60 depicts a side, cross-sectional view of an exemplary device tipcoupled to a slidable shield by an interference fit.

FIGS. 61A-61B show partial cross-sectional views of another exemplaryinjector attachment.

FIGS. 62A-62B depict another injection device according to a furthervariation. FIG. 62A is a side view that shows some internal features ofthe device. FIG. 62B is an expanded cross-sectional view of the devicetip.

FIGS. 63A-63B depict another variation of the device clip and how itfunctions to prevent and allow movement of a slidable sleeve.

FIG. 64 is a graph that compares the needle bend and recovery forces ofan exemplary needle having a needle stabilization mechanism tocommercially available needles.

FIG. 65 depicts an exemplary system for drug delivery that includes aflexible arm connector for controlling the position and angle of a leverof an injection device, a priming-enabling component, and an internalluer seal.

FIGS. 66A-66C depict exemplary priming-enabling components.

DETAILED DESCRIPTION

Described here are hand-held devices, methods, and systems fordelivering, e.g., by injection, pharmaceutical formulations into theeye. The devices may integrate (combine) various features that may bebeneficial in delivering the pharmaceutical formulations into the eye,e.g., in a safe, sterile, and accurate manner, into a single device.That is, the devices may have a modular design. As used herein, the term“modular” refers to a device formed from a combination of variouscomponents that are capable of being attached to, and detached from, thedevice housing. For example, e.g., various resistance components,filters (e.g., a hydrophilic and/or hydrophobic filter combination),ocular measuring components, etc., may be configured asattachable/detachable components that can be combined with a syringehousing. Thus, features that may aid appropriate placement on the eye,help positioning so that the intraocular space is accessed at the properangle and/or depth, adjust or control ocular wall tension, and/or helpto minimize trauma to the sclera and intraocular structures, e.g., fromthe force of injection or penetration of the sclera itself, may beintegrated into a single device. The devices, in whole or in part, maybe configured to be disposable. The devices may also be configured toremove air, infectious agents, and/or particulate matter fromformulations or compositions prior to their injection into the eye. Forexample, it may be advantageous to remove air from compositionscomprising ranibizumab or other viscous compositions prior to injectionof these compositions into the eye. This is so that the risk of thepatient developing visual disturbances such as floaters can beeliminated or minimized.

I. Devices

In general, the integrated or modular devices described here include ahousing sized and shaped for manipulation with one hand. The housingtypically has a proximal end and a distal end, and an ocular contactsurface at the housing distal end. A conduit tin its pre-deployed statemay reside within the housing. The conduit will be at least partiallywithin the housing in its deployed state. In some variations, theconduit is slidably attached to the housing. Additionally, the conduitwill generally have a proximal end, a distal end, and a lumen extendingtherethrough. An actuation mechanism may be contained within the housingthat is operably connected to the conduit and a reservoir for holding anactive agent.

The devices or portions thereof may be formed from any suitablebiocompatible material or combination of biocompatible materials. Forexample, one or more biocompatible polymers may be used to make, e.g.,the device housing, ocular contact surface, measuring component, needlehub, slidable shield, safety clip, plunger, plunger seal, side plungertrigger-actuator, etc. Exemplary biocompatible materials include withoutlimitation, methylmethacrylate (MMA), polymethylmethacrylate (PMMA),polyethylmethacrylate (PEM), and other acrylic-based polymers;polyolefins such as polypropylene and polyethylene; vinyl acetates;polyvinylchlorides; polyurethanes; polyvinylpyrollidones;2-pyrrolidones; polyacrylonitrile butadiene; polycarbonates (e.g.,polished polycarbonate and glass filled polycarbonate); polyamides;fluoropolymers such as polytetrafluoroethylene (e.g., TEFLON™ polymer);polystyrenes; styrene acrylonitriles; cellulose acetate; acrylonitrilebutadiene styrene; polymethylpentene; polysulfones; polyesters;polyimides; natural rubber; polyisobutylene rubber; polymethylstyrene;silicone; thermoplastic elastomers such as Medalist® TPE (e.g., TPEMD-100 (5 durometer Shore A), TPE MD-105 (18 durometer Shore A), TPEMD-145 (50A durometer) and TPE MD-555 (55 A durometer), and otherthermoplastic elastomers having a durometer between about 2 A and 70 A,between about 40 A and 70 A, or between about 5 A and 60 A); andcopolymers and blends thereof.

In some variations, the device or a portion of the device such as thedrug reservoir, plunger, housing, ocular contact surface, or measuringcomponent, is made of a material that includes a cyclic olefin seriesresin. Exemplary cyclic olefin resins include without limitation,commercially available products such as Zeonex® cyclo olefin polymer(ZEON Corporation, Tokyo, Japan) or Crystal Zenith® olefinic polymer(Dalkyo Seiko, Ltd., Tokyo, Japan) and APEL™ cyclo olefin copolymer(COC) (Mitsui Chemicals, Inc., Tokyo, Japan), a cyclic olefin ethylenecopolymer, a polyethylene terephthalate series resin, a polystyreneresin, a polybutylene terephthalate resin, and combinations thereof. Inone variation, it may be beneficial to use a cyclic olefin series resinand a cyclic olefin ethylene copolymer that have high transparency, highheat resistance, and minimal to no chemical interaction with apharmacological product such as a protein, a protein fragment, apolypeptide, or a chimeric molecule including an antibody, a receptor ora binding protein.

The cyclic olefin polymers or the hydrogenation products thereof can bering-opened homopolymers of cyclic olefin monomers, ring-openedcopolymers of cyclic olefin monomers and other monomers, additionhomopolymers of cyclic olefin monomers, addition copolymers of cyclicolefin monomers and other monomers, and hydrogenation products of suchhomopolymers or copolymers. The above cyclic olefin monomers may includemonocyclic olefin monomers, and polycyclic olefin monomers includingbicyclic and higher cyclic compounds. Examples of the monocyclic olefinmonomers suitable for the production of the homopolymers or copolymersof the cyclic olefin monomers are monocyclic olefin monomers such ascyclopentene, cyclopentadiene, cyclohexene, methylcyclohexene andcyclooctene; lower-alkyl derivatives thereof containing, as substituentgroups, 1 to 3 lower alkyl groups such as methyl and/or ethyl groups;and acrylate derivatives thereof.

Examples of the polycyclic olefin monomers are dicyclopentadiene,2,3-dihydrocyclopentadiene, bicyclo[2,2,1]-hepto-2-ene and derivativesthereof, tricyclo[4,3,0,1^(2,5)]-3-decene and derivatives thereof,tricyclo[4,4,0,1^(2,5)]-3-undecene and derivatives thereof,tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene and derivatives thereof,pentacyclo[6,5,1,1^(3,6),0^(2,7),0^(9,13) 4-pentadecene and derivativesthereof, pentacyclo[7,4,0,1^(2,5,0),0^(8,13),1^(9,12)]-3-pentadecene andderivatives thereof, andhexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7)0^(9,14)]-4-heptadecene andderivatives thereof. Examples of bicyclo[2,2,1]-hepto-2-ene derivativesinclude 5-methyl-bicyclo[2,2,1]-hepto-2-ene,5-methoxy-bicyclo[2,2,1]-hepto-2-ene,5-ethylidene-bicyclo[2,2,1]-hepto-2-ene,5-phenyl-bicyclo[2,2,1]-hepto-2-ene, and6-methoxycarbonyl-bicyclo[2,2,1-]-hepto-2-ene. Examples oftricyclo[4,3,0,1^(2,5)]-3-decene derivatives include2-methyl-tricyclo[4,3,0,1^(2,5)]-3-decene and5-methyl-tricyclo[4,3,0,1^(2,5)]-3-decene. Examples oftetracyclo[4,4,0,1^(2,5)]-3-undecene derivatives include10-methyl-tetracyclo[4,4,0,1^(2,5)]-3-undecene, and examples oftricyclo[4,3,0,1^(2,5)]-3-decene derivatives include5-methyl-tricyclo[4,3,0,1^(2,5)]-3-decene.

Examples of tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene derivativesinclude 8-ethylidene-tetracyclo-[4,4,0,1^(2,5)0^(7,10)]-3-dodecene,8-methyl-tetracyclo-[4,4,0,1^(2,5),0^(7,10)]-3-dodecene,9-methyl-8-methoxy-carbonyl-tetracyclo[4,4,0,1^(2,5)0^(7,10)]-3-dodecene,5,10-dimethyl-tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene. Examples ofhexacyclo[6,6,1,^(3,6),1^(10,13),0^(2,7), 0^(9,14)]-4-heptadecenederivatives include12-methyl-hexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7),0^(9,14)]-4-heptadeceneand1,6-dimethyl-hexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7),0^(9,14)]-4-heptadecene.One example of the cyclic olefin polymer is an addition homopolymer ofat least one cyclic olefin monomer or an addition copolymer of at leastone cyclic olefin monomer and at least one other olefin monomer (forexample, ethylene, propylene, 4-methylpentene-1, cyclopentene,cyclooctene, butadiene, isoprene, styrene, or the like). Thishomopolymer or copolymer can be obtained by polymerizing the abovemonomer or monomers, for example, while using as a catalyst a knowncatalyst which is soluble in a hydrocarbon solvent and is composed of avanadium compound or the like and an organoaluminum compound or the like(Japanese Patent Application Laid-Open (Kokai) No. HEI 6-157672,Japanese Patent Application Laid-Open (Kokai) No. HEI 5-43663).

Another example of the cyclic olefin polymer is a ring-openedhomopolymer of the above monomer or a ring-opened copolymer of the abovemonomers. It can be obtained by homopolymerizing the above monomer orcopolymerizing the above monomers, for example, while using as acatalyst a known catalyst such as (1) a catalyst composed of a halide orthe nitrate of a platinum group metal such as ruthenium, rhodium,palladium, osmium or platinum and a reducing agent or (2) a catalystcomposed of a compound of a transition metal such as titanium,molybdenum or tungsten and an organometal compound of a metal in one ofGroups I to IV of the periodic table such as an organoaluminum compoundor organotin compound (Japanese Patent Application Laid-Open (Kokai) No.HEI 6-157672, Japanese Patent Application Laid-Open (Kokai) No. HEI5-43663).

The homopolymer or copolymer may contain unsaturated bonds. Thehomopolymer or copolymer may be hydrogenated using a known hydrogenationcatalyst. Examples of the hydrogenation catalyst include (1)Ziegler-type homogeneous catalysts which are each composed of an organicacid salt of titanium, cobalt, nickel or the like and an organometalcompound of lithium, aluminum or the like, (2) supported catalysts whichare each composed of a carrier such as carbon or alumina and a platinummetal such as palladium or ruthenium supported on the carrier, and (3)catalysts which are each composed of a complex of one of theabove-described platinum group metal (Japanese Patent ApplicationLaid-Open (Kokai) No. HEI 6-157672).

In variations where the injection device includes a plunger, the plungerseal (plunger tip) may be made from a thermoplastic elastomer aspreviously described and coated with a silicone fluid such as a DowCorning® 360 Medical Fluid, e.g., polydimethylsiloxane. Some variationsof the plunger seal may be coated with a fluoropolymer instead of asilicone polymer. Exemplary fluoropolymer coatings may comprisepolytetrafluoroethylene, fluorolene, fluoroglide, and combinationsthereof. Other silicone-free coatings may also be used. When the plungerseal is uncoated, it may be made from polypropylene, polyethylene, or acyclic olefin resin, or any modifications thereof. In other variations,the inner surface of the barrel is coated. The coatings here may be thesame as the ones mentioned for the plunger seal. It may be useful toinclude a coating on the plunger seal, inner surface of the barrel, orboth, because it may impart a predictable and constant plunger release(from a resting position) and travel/glide force (force required toadvance the plunger through the barrel). Employment of a coating mayresult in a zero or near-zero break force (force required to startadvancement of the plunger from a resting position). For example, when acoating is used, the break force may be equal to the travel force, ormay be up to about 10 gm more than the travel force. Having a breakforce of zero, near-zero, or any one of the values mentioned above, mayprevent an initial burst of fluid being injected into the eye that couldpotentially cause fluid waves and injure intraocular structures such asthe retina. The coatings may help to prevent high, variable, and/orunpredictable initial plunger resistance, especially after prolongedstorage.

In some variations, the device or a portion of the device such as thedrug reservoir is made of a material that comprises polypropylene,polyethylene, or a rubber. Examples of suitable rubber materials includebutyl rubbers such as butyl rubber, chlorinated butyl rubber, brominatedbutyl rubber, and divinylbenzene-copolymerized butyl rubber; conjugateddiene rubbers such as polyisoprene rubber (high to low cis-1,4 bond),polybutadiene rubber (high to low cis-1,4 bond), and styrene-butadienecopolymer rubber; and ethylene-propylene-diene terpolymer rubber (EPDM).Crosslinkable rubber materials may also be used, and may be made bykneading the above-described rubber materials together with additivessuch as a crosslinking agent, a filler and/or reinforcement, a colorant,or an age resister.

In some variations, the biocompatible material is a biodegradablepolymer. Non-limiting examples of suitable biodegradable polymersinclude cellulose and ester, polyacrylates (L-tyrosine-derived or freeacid), poly(β-hydroxyesters), polyamides, poly(amino acid),polyalkanotes, polyalkylene alkylates, polyalkylene oxylates,polyalkylene succinates, polyanhydrides, polyanhydride esters,polyaspartimic acid, polylactic acid, polybutylene digloclate,poly(caprolactone), poly(caprolactone)/poly(ethylene glycol) copolymers,polycarbone, L-tyrosin-derived polycarbonates, polycyanoacrylates,polydihydropyrans, poly(dioxanone), poly-p-dioxanone,poly(ε-caprolactone-dimethyltrimethylene carbonate), poly(esteramide),polyesters, aliphatic polyesters, poly(etherester), polyethyleneglycol/poly(orthoester) copolymers, poly(glutarunic acid), poly(glycolicacid), poly(glycolide), poly(glycolide)/poly(ethylene glycol)copolymers, poly(lactide), poly(lactide-co-caprolactone),poly(DL-lactide-co-glycolide), poly(lactide-co-glycolide)/poly(ethyleneglycol) copolymers, poly(lactide)poly(ethylene glycol) copolymers,polyphosphazenes, polyphosphesters, polyphophoester urethanes,poly(propylene fumarate-co-ethylene glycol), poly(trimethylene carbone),polytyrosine carbonate, polyurethane, terpolymer (copolymers ofglycolide lactide or dimethyltrimethylene carbonate), and combinations,mixtures or copolymers thereof.

Additives may be added to polymers and polymer blends to adjust theirproperties as desired. For example, a biocompatible plasticizer may beadded to a polymer formulation used in at least a portion of a device toincrease its flexibility and/or mechanical strength, or to provide colorcontrast with respect to the surface of the eye. In other instances, abiocompatible filler such as a particulate filler, fiber and/or mesh maybe added to impart mechanical strength and or rigidity to a portion of adevice.

The devices described here can be manufactured, at least in part, byinjection or compression molding the above-described materials.

In some instances, it may be beneficial to include a removably attachedor integrated viewing and/or magnifying element on the device. Forexample, a magnifying glass and/or illumination source such as a LEDlight may be removably attached to the device to facilitate thevisualization of the tip of the device and the injection site. Theimproved visualization may help to more precisely and safely positionthe device at a target location, e.g., about 3.5 mm to 4 mm posterior tothe corneo-scleral limbus, so that complications of intraocularinjection such as retinal detachment, ciliary body bleeding, or traumato the intraocular lens can be potentially avoided. The magnifying glassmay be made from any suitable material, e.g., it may be made from anysuitable non-resorbable (biodegradable) material previously described,but will typically be light-weight so that it does not affect thebalance of the injection device. The magnifying glass and/orillumination source, e.g., the LED, may be disposable.

Housing

The housing of the device generally contains the drug reservoir andactuation mechanism. In its first, non-deployed state (pre-deployedstate), the conduit may reside within the housing. The housing may be ofany suitable shape, so long as it allows grasping and manipulation ofthe housing with one hand. For example, the housing may be tubular orcylindrical, rectangular, square, circular, or ovoid in shape. In somevariations, the housing is tubular or cylindrical, similar to the barrelof a syringe. In this instance, the housing has a length between about 1cm and about 15 cm, between about 2.5 cm and about 10 cm, or about 4 cmand about 7.5 cm. For example, the housing may have a length of about 1cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about13 cm, about 14 cm, or about 15 cm. The surface of the housing may alsobe texturized, roughened, or otherwise modified in certain areas, e.g.,with protrusions, ridges, etc., to aid the grip and or manipulation ofthe housing by the user. Grips may be associated with any one of theactuation mechanisms further described below. The grips are generallyconfigured to help the operator maintain a steady grip on the deviceusing, e.g., two, three or four fingers. The plunger actuation lever maybe located on the device housing in the close proximity of the grip, forexample, integrated with the grip, or between about 1.0 mm and 10 mm ofthe grip, so that the operator is able to easily use the fingers holdingthe device to actuate, e.g., slide, the actuation lever whilemaintaining a steady grip and without compromising the hold/control ofthe device. The distance that the actuation lever may travel may bebetween about 2.0 mm and about 8.0 mm, or between about 1.0 mm and about15 mm). Maintaining a steady grip while actuating the drug injectionmechanism is useful because it helps to localize the injection site onthe eye surface with about a 0.5 mm precision accuracy.

In some variations, the housing comprises a syringe barrel having adistal end that includes a luer. The luer may be of any suitable type,e.g., slip-tip, luer-lock, or luer-snap type. When the luer is of theluer lock type, it may interface with a drug conduit by twisting thedrug conduit on/off. When the luer is of the luer-snap type, it maycomprise a raised edge on the outside surface of the luer tip that mayinterlock with a raised ridge located on the inside surface of the hubof a drug conduit to form a male-female type of connection. Theluer-snap connection may enhance the connection strength between thehousing (having a reservoir disposed within) and a drug conduit ascompared to the slip-tip type of connection, but without the rigid lockthat is achieved with a luer-lock type of connection.

Some variations of the luer-snap connector may provide tactile feedbackto ensure that the drug conduit has been appropriately positioned andstably interfaced with the housing (e.g., that the hub of the drugconduit has been placed far enough onto the luer to prevent itsaccidental detachment during the drug injection procedure.

The luer-snap connector may further comprise a self-positioningmechanism to ensure the hub of the drug conduit has been stablypositioned in the right location on the luer. The self-positioningmechanism may be a combination of interlocking raised ridges, where oneridge is located on the external surface of the luer and the other ridgeis located on the internal surface of the drug conduit hub, but at leastone of the ridges has a shallow leading slope and a steep trailing slopethat may allow the drug conduit to self-position and snap into placeonce the ridges have been advanced past each other.

The housing may be made from any suitable material. For example, and aspreviously stated, the components of the device may be made from anysuitable biocompatible material or combination of biocompatiblematerials. Materials that may be beneficial in making the housinginclude, without limitation, a cyclic olefin series resin, a cyclicolefin ethylene copolymer, a polyethylene terephthalate series resin, apolystyrene resin, and a polyethylene terephthalate resin. In onevariation, it may be beneficial to use a cyclic olefin series resin anda cyclic olefin ethylene copolymer that have a high transparency, a highheat resistance, and minimal to no chemical interaction with apharmacological product such as a protein, a protein fragment, apolypeptide, or a chimeric molecule including an antibody, a receptor ora binding protein. Additional materials that may be beneficial in makingthe housing include, without limitation, fluoropolymers; thermoplasticssuch as polyetheretherketone, polyethylene, polyethylene terephthalate,polyurethane, nylon, and the like; and silicone. In some variations, thehousing may be made from a transparent material to aid confirmation ofconduit deployment and/or drug delivery. Materials with suitabletransparency are typically polymers such as acrylic copolymers,acrylonitrile butadiene styrene (ABS), polycarbonate, polystyrene,polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG), andstyrene acrylonitrile (SAN). Acrylic copolymers that may be usefulinclude, but are not limited to, polymethyl methacrylate (PMMA)copolymer and styrene methyl methacrylate (SMMA) copolymer (e.g., Zylar631® acrylic copolymer).

Ocular Contact Surfaces

The devices described herein generally include an atraumatic ocularcontact surface at the distal end of the housing. In some variations,the ocular contact surface is fixedly attached to the housing proximalend. In other variations, the ocular contact surface is removablyattached to the housing proximal end. The ocular contact surface willtypically be sterile. In some instances, the ocular contact surface isdisposable. In use, the ocular contact surface of the device is placedon the surface of the eye.

The ocular contact surface may be of any suitable configuration, e.g.,size, shape, geometry, etc., as long as it allows atraumatic placementof the device on the ocular surface. In some variations, the ocularcontact surface is ring-shaped (e.g., FIGS. 1A-1B). When the ocularcontact surface takes the shape of a ring, it may have a diameter ofabout 0.3 mm to about 8 mm, about 1 mm to about 6 mm, or about 2 mm toabout 4 mm. In other variations, the ocular contact surface is oval orcircular in shape.

More specifically, as shown in the front views of FIGS. 1A-1B, thedevice tip comprises a ring-shaped ocular contact surface where thedistance between the inner diameter and outer diameter of the ring formsa rim. In this instance, the ring-shaped ocular contact surface may beconfigured as having a wider ocular contact surface (10) (rim) andsmaller internal opening (12) (FIG. 1A), or narrower ocular contactsurface (14) (rim) with larger internal opening (16) (FIG. 1B). Thedispensing member (conduit) may be an injection needle that is hiddeninside and protected by the device tip. A membrane may also be providedthat extends across the internal opening, and which may be flush withthe ocular contact surface or recessed within the lumen of the devicetip where the injection needle resides.

As shown in FIGS. 39A-39B, the tip of the dispensing member may berecessed relative to end of the device housing tip comprising the ocularcontact surface in the resting state, so that when the device tip isplaced in contact with any surface such as the skin or the eye wall, thetip of the dispensing member is separated from the surface by a distancemarked with arrows in FIG. 39B. This distance may ensure that thedispensing member tip does not come in direct contact with any surfaceprior to the injection procedure, which prevents accidental bacterialcontamination of the dispensing member from sources such as skinsecretions, ocular secretions or tears, and minimizes the risk ofintroducing intraocular infectious agents during the intraocularinjection procedure that may cause endophthalmitis.

In some variations, the tip of the dispensing member is recessedrelative to, and is separated from the closest end of the device housingby a distance ranging from about 0.01 mm to about 10 mm, from about 0.1mm to about 5 mm, or from about 0.5 mm to about 2 mm.

An enclosure may be provided on the distal end of the device thatcompletely covers the dispensing member to prevent it from contactingeye lashes or eye lids, and to prevent it from being exposed topotentially contaminated surfaces at all times. Here the dispensingmember may extend from the enclosure and penetrate the eye wall and intoan eye cavity without being exposed to ocular appendages such as eyelidsor eye lashes that harbor bacteria. The eye is an immune-privilegedorgan and, thus, any bacterial contamination has the propensity toresult in intraocular infection. Enclosure of the dispensing member mayprotect it from contacting ocular appendages harboring bacteria, therebyminimizing the risk of sight-threatening intraocular infection. In onevariation, the dynamic sleeve (further described below) is configured asthe sterile enclosure. The dynamic sleeve may also be covered by amembrane that prevents ocular surface tears from entering the orifice ofthe device tip and potentially contaminating the dispensing memberbefore it is deployed.

In other variations, the outer surface of the device tip may beconfigured to include a raised surface that forms a seal around the exitsite of the dispensing member from the device tip. The seal may functionto prevent ocular tears from circulating through the potential injectionsite once the device tip has been positioned on the eye surface. Theraised surface may be configured to be annular, oval, square,rectangular, triangular or any other suitable shape or geometry.

In another variation, the ocular contact surface of the device tip thatcomes in direct contact with the eye surface is ring-shaped, where thereis a clearing between the internal wall of the device housing and thedispensing member of about 360 degrees, which is marked by arrows inFIG. 39C. Here, if the ring-shaped ocular interface surface becomescontaminated with an infectious agent and is placed onto the eyesurface, the dispensing member will come in contact and penetratethrough the eye surface that is separated from the contaminated devicetip by the area of clearing, which prevents accidental bacterialcontamination of the dispensing member and minimizes the risk ofintroducing intraocular infection that may cause endophthalmitis. Incontrast, the lack of such clearing around the dispensing member, asshown in FIG. 39D, may allow accidental infectious contamination of thedevice tip at the site of injection.

In some variations, there is a clearing between the internal wall of thedevice housing and the dispensing member ranging from about 0.1 mm toabout 5 mm, from about 0.3 mm to 3 mm, or from about 0.5 mm to about 2mm.

In other variations, there is a solid membrane or partition (105) thatseparates the tip of the dispensing member (107) from the externalenvironment, as shown in FIG. 39E, where the membrane or partition maybe water-impermeable and/or be air-impermeable. The membrane orpartition may ensure that there is no air movement in or out of thedevice creating an air seal and maintaining a certain constant airpressure inside the device.

Furthermore, the membrane or partition may ensure that the dispensingmember tip does not come in contact with any source of accidentalbacterial contamination such as tears and ocular secretions prior to theinjection procedure, which prevents accidental bacterial contaminationof the dispensing member and minimizes the risk of introducingintraocular infection during the intraocular injection procedure thatmay cause endophthalmitis.

The membrane or partition that separates the tip of the dispensingmember from the end of the device housing may comprise a materialselected from the group consisting of biocompatible andnon-biodegradable materials including without limitation,methylmethacrylate (MMA), polymethylmethacrylate (PMMA),polyethylmethacrylate (PEM), and other acrylic-based polymers;polyolefins such as polypropylene and polyethylene; vinyl acetates;polyvinylchlorides; polyurethanes; polyvinylpyrollidones;2-pyrrolidones; polyacrylonitrile butadiene; polycarbonates; polyamides;fluoropolymers such as polytetrafluoroethylene (e.g., TEFLON™ polymer);or fluorinated ethylene propylene (FEP); polystyrenes; styreneacrylonitriles; cellulose acetate; acrylonitrile butadiene styrene;polymethylpentene; polysulfones; polyesters; polyimides; natural rubber;polyisobutylene rubber; polymethylstyrene; silicone; derivatives andcopolymers and blends thereof.

In some variations, the membrane or partition (30) may be recessedinside the device tip so that when the device tip is placed in contactwith any surface such as the skin or the eye surface, the said membraneor partition is separated from the said surface by a distance markedwith arrows, as depicted in FIG. 39E. The distance may ensure that thedispensing member tip (31) does not come in direct contact with anysurface prior to the injection procedure, which prevents accidentalbacterial contamination of the dispensing member from sources such asskin secretions, ocular secretions or tears, and minimizes the risk ofintroducing intraocular infection during the intraocular injectionprocedure that may cause endophthalmitis.

The membrane or partition may be recessed relative to and separated fromthe end of the device housing at the ocular interface by a distanceranging from about 0.01 mm to about 10 mm, from about 0.1 mm to about 5mm, or from about 0.5 mm to about 2 mm.

In further variations, a measuring component (32) (further describedbelow) may be recessed relative to the end of the device housing (33) atthe ocular contact surface (FIGS. 39F-39H), so that when the device tip(34) comes in contact with the eye surface (35) (FIG. 39I), themeasuring component (32) does not come in contact with the eye surface(35). This configuration may minimize the risk of trauma to the delicatetissue covering the eye surface such as the non-keratinizing epitheliaof the cornea and conjunctiva. Avoiding direct contact between themeasuring member and the ocular surface may be beneficial in minimizingthe risk of ocular surface trauma such as corneal or conjunctivalabrasion, which prevents further serious complications such as bacterialinjection including corneal ulcer. In alternative variations, the tip ofthe measuring member (32) may be angled away or towards the eye (FIGS.39G and 39H, respectively). The measuring component may be recessedrelative to the end of the device housing by a distance ranging fromabout 0.01 mm to about 5 mm, from about 0.1 mm to about 3 mm, or fromabout 0.5 mm to about 2 mm.

In some variations, as shown in FIGS. 2A-2C, the device tip may alsocomprise a ring-shaped ocular contact surface and a measuring means thathelps to determine the proper location of the injection site at acertain distance relative to and perpendicular to the corneo-sclerallimbus. In one variation, the measuring component (20) is located on oneside of the device tip (22). In another variation, more than onemeasuring component is located on more than one side of the device tip.Here the tip of the measuring component is flat (FIG. 2C) and does notsubstantially protrude above the ocular contact surface. In othervariations, the tip of the measuring component is raised (FIGS. 2A-2B)above the ocular contact surface, which enables it to prevent the eyelidfrom sliding over and on top of the measuring component, thus preventingthe eyelid from coming into contact with the sterile ocular contactsurface of the device tip or the dispensing member. This in turn mayreduce the risk of accidental contamination and intraocular infectionduring the injection procedure.

In other variations, the ocular contact surface comprises a flange(e.g., FIGS. 3A1-3A3, FIGS. 3B1-3B3, FIG. 4A, and FIGS. 4B1-4B2). Theflange may provide an expanded contact surface between the device tipand the eye surface, thus increasing the stability of the device when itis positioned on the ocular surface, and decreasing the pressure forceper unit area of the device-ocular interface. Reducing the pressureforce per unit area of the device-ocular interface in turn may reducethe potential for conjunctival damage by the device tip when it ispressed against the eye wall. Avoiding such conjunctival damage isdesirable because the conjunctiva is covered by delicatenon-keratinizing epithelium containing multiple sensory nerve endingsand pain receptors.

In some variations, the flange may have thin edges that come in contactwith the ocular surface, and which allows the eye lid to travel over andon top of the flange, but prevents the eye lid from coming in contactwith the sterile ocular contact surface of the device tip. The ocularcontact surface may also be a ring-shaped flange (e.g., FIGS. 4A and4B1-4B2). Such a ring-shaped flange may also prevent the eye lid fromcoming in contact with the sterile ocular contact surface of the devicetip.

More specifically, as shown in FIG. 3, the flange may have a thin edge(FIG. 3A1), which allows the eye lid to slide over the said flange andcome in contact with the shaft of the device tip. In an alternativevariation, the said flange may be thick (FIG. 3B1) in order to preventthe eye lid from sliding over it and keeping it from coming in contactwith the device shaft, thus preventing inadvertent contamination of theinjection site. When the flange at the ocular contact surface of thedevice tip is thick, its edges, such as those at its ocular surface maybe rounded in order to prevent accidental damage to the ocular surfacetissues such as the conjunctiva that is covered with delicatenon-keratinizing epithelium rich in nerve endings and pain receptors. Inalternative variations of the device tip, the ocular contact interfacemay be flat (FIGS. 3A1 and 3B1), convex (FIGS. 3A2 and 3B2), or concave(FIGS. 3A3 and 3B3) to reduce the chance of accidental damage to ocularsurface tissues such as the conjunctiva while providing a means ofapplying a force onto the eye wall and increasing intraocular pressurein order to facilitate the needle penetration through the eye wall, aswell as to partially immobilize the eye during the injection procedureby providing the traction interface of the ocular contact surface. FIGS.4A and 4B1-4B2 illustrate perspective and front views of a flangedocular contact surface.

In yet further variations, the ocular contact surface may be configuredto be flat, convex, concave, or slanted (e.g., FIGS. 5 and 7). In FIGS.5A1-5A2, the device tip has a flat ocular contact surface. In analternative variation, the device tip has a protruding or convex ocularcontact surface (FIGS. 5B1-5B2), which may improve contact between theinternal opening of the device tip and the ocular surface when thedevice tip is pressed against the eye wall resulting in eye wallindentation. In yet another variation, the ocular contact surface of thedevice tip is indented or concave, which reduces the risk of accidentaldamage to the ocular surface tissue such as the conjunctiva. Suchconfigurations of the ocular contact surface of the device tip mayreduce the chance of accidental damage to ocular surface tissues, suchas the conjunctiva, while providing a means of applying a pressure forceonto the eye wall and increasing the intraocular pressure in order tofacilitate the needle penetration through the eye wall, as well as topartially immobilize the eye during the injection procedure by providingthe device-ocular surface traction interface.

More specifically, as shown in FIG. 7, the ocular contact surface may beflat and perpendicular to the long axis of the said device (FIGS.7A1-7A2), or is flat and slanted relative to the long axis of the saiddevice (7B1-7B2) (e.g., oriented at an angle other than 90 degrees, suchas from about 45 degrees to about 89 degrees relative to the long axisof the device), or is convex and perpendicular to the long axis of thedevice (FIG. 7C1), or is convex and slanted relative to the long axis ofthe device (FIG. 7C2), or is rounded (FIG. 7D), or is oval (FIG. 7E). Inone variation, the ocular interface is rounded or oval (e.g., similar tothe tip of a Q-tip). The thickness of the ocular contact surface may befrom about 0.01 mm to about 10 mm, from about 0.05 mm to about 5 mm, orfrom about 0.1 mm to about 2 mm.

The ocular contact surface may include one or more features (e.g.,slip-reducing features) that help to stabilize it on the eye surface(e.g., prevent slippage on the eye surface). For example, in onevariation, the ocular contact surface comprises one or a plurality oftraction elements, e.g., bumps, ridges, raised details above the planeof the ocular contact surface, etc., that increase surface traction ofthe ocular contact surface on the eye surface without being abrasive.Such an ocular contact surface may provide a mild-, medium-, orhigh-traction interface to stabilize the device tip on the surface ofthe eye and prevent it from moving during intraocular drug delivery. Inanother variation, the ocular contact surface includes an adherentinterface such as a suction mechanism. Varying the type of material usedto make the ocular contact surface may also help prevent its slippage onthe ocular surface.

The materials used to make the ocular contact surface may also help toprevent abrasion, scratching, or irritation of the eye surface.Exemplary non-abrasive materials that may be employed include withoutlimitation, nylon fiber, cotton fiber, hydrogels, spongiform materials,styrofoam materials, other foam-like materials, silicone, plastics,PMMA, polypropylene, polyethylene, fluorinated ethylene propylene (FEP),and polytetrafluoroethylene (PTFE). Thermoplastic elastomers (TPEs),e.g., silicone, may be beneficial to use when making the ocular contactsurface. The materials may be smooth-hard, semi-hard, or soft, and maybe beneficial in preventing conjunctival abrasion, subconjunctivalhemorrhage during transcleral needle deployment, or other accidentaltrauma to the ocular surface tissues (FIG. 6). For example, the materialof the ocular contact surface may have a durometer ranging between about2 A and about 70 A or from about 30 A and about 60 A. Materialstypically used in contact lens manufacturing may also be employed.

In some variations, the edges of the ocular contact surface are alsorounded to prevent accidental damage to the ocular surface tissues suchas the conjunctiva that is covered with delicate non-keratinizingepithelium rich in nerve endings and pain receptors. In this instance,as shown in FIG. 6, the ocular contact surface may have a circumferencecorresponding to the circumference of the device tip (FIGS. 6A1-6A2). Inother variations, the circumference of the ocular contact surface mayprotrude beyond the circumference of the shaft of the device tip, thusforming a flange (FIGS. 6B1-6B2). The flange may increase the ocularcontact surface of the device tip while maintaining the slim profile ofthe shaft of the tip, enabling its easy insertion into theinterpalprebral fissure of the eye.

The ocular contact surface may also provide an interface surface that ispliable or deformable, and which conforms to the surface of the eye whenplaced against the said eye surface during the intraocular drug deliveryprocedure. The surface of the eye that comes in direct contact with thesaid interface surface of the disclosed device includes, but is notlimited to, the surface of the eye over the pars plana region defined asthe circumferential area between about 2 mm and 7 mm posterior to andsurrounding the limbus, or the corneo-scleral limbal area between about2 mm anterior and about 2 mm poster to and circumferential to thelimbus. The interface surface that conforms to the curvature of thesurface of the eye may enable the formation of an optimal contactinterface between the device and the eye, and may ensure sterility ofthe intraocular drug delivery process and immobilization of the eye,which in turn may enhance the safety of the injection procedure.Examples of ocular interface materials for the device are those that aregenerally able to conform to the surface of the eye (that is deformableor pliable) particularly to the curvature of the external surface of theeye in the area of pars plana about 2-5 mm posterior to thecorneo-scleral limbus for intravitreal drug application, as well as tothe area of the corneo-scleral limbus for anterior chamber drugapplications. As previously stated, materials that are non-abrasive tothe non-keratinizing conjunctival and corneal epithelium of the ocularsurface may be used. Specifically, the materials and theirconfigurations (e.g., foam, braid, knit, weave, fiber bundle, etc.), mayinclude those capable of forming medium- or high-traction surfaces(e.g., hydrogels or cotton) that enable immobilization of the eye globeduring the injection procedure.

In some variations, the material of the ocular contact surface changesits properties upon contact with fluid, e.g., by reducing its tractioncoefficient such as in cotton fiber, which may reduce the risk ofconjunctival abrasion upon contact of the ocular contact surface withthe eye surface. In other variations, the material comprising ocularcontact surface does not change its physical and chemical propertieswhen exposed to fluid that covers the surface of the eye such as tears.

The ocular contact surfaces described here may be beneficial inpreventing conjunctival and/or episcleral bleeding during intraocularneedle injection. For example, a device comprising a ring-shaped ocularinterface may be pressed against the eye wall, which in turn appliespressure to the conjunctival and episcleral vessels, thereby reducingblood flow therethrough. Given the reduced blood flow through thesevessels, the risk of subconjunctival bleeding during intraocularinjection procedure may be reduced. Following the completion ofintraocular drug application, the needle is withdrawn, but thering-shaped tip may remain pressed against the eye wall, thus applyingcontinuous pressure onto the conjunctival and episcleral vessels andfurther reducing the risk of bleeding and/or minimizing the extent ofbleeding.

In some variations, the device comprises an ocular contact surface thatfunctions as a drug reservoir. Here a drug may be incorporated into, orcoated on, the material of the ocular contact surface. The drug may thendiffuse, leech, etc., from the ocular contact surface onto the surfaceof the eye. Exemplary materials for inclusion of drugs are hydrogels andtheir derivatives.

The ocular contact surface may also cover the dispensing member(conduit) such as an injection needle (e.g., it may be a cap thatentirely covers the needle), which may enable the injector to applypressure onto the eye by pressing the tip (e.g., the distal end of thecap) against the eye wall. This in turn may increase the intraocularpressure before the needle comes in contact with the eye wall and, thus,may facilitate needle penetration because the eye wall is more taut incomparison to an eye wall being penetrated by a needle on a conventionalsyringe. Needle penetration is typically more difficult with aconventional syringe because the lower intraocular pressure that isgenerated makes the eye wall more deformable and mobile. In addition,the device tip that covers the dispensing member (conduit), such as aninjection needle, may also protect the said dispensing member from beingcontaminated by its accidental contact with eye lids. The cover may bemade from any suitable material. Exemplary materials include withoutlimitation, polyethylene, polycarbonate, polypropylene, acrylonitrilebutadiene styrene polymers, Delrin® acetal homopolymers, polyurethane,acrylic polymers, polyether ether ketone, and combinations thereof. Inone variation, the cover is made from polycarbonate.

Intraocular Pressure Control Mechanisms (Ocular Wall Tension ControlMechanisms)

The control of intraocular pressure (IOP) during the drug deliveryprocedure, e.g., intraocular injection or intravitreal injection, may bebeneficial. The application of limited intraocular pressure beforedeployment of the dispensing member (conduit) may reduce scleralpliability, which in turn may decrease any unpleasant sensation on theeye surface during an injection procedure and/or prevent backlash of thedevice. The term “backlash” typically refers to the inability of theconduit to smoothly penetrate the eye wall due to scleral pliability andelasticity, which makes the sclera indent to a certain point and pushthe conduit and device backwards before the conduit penetrates into andthrough the sclera. Accordingly, the devices described here may includeone or more IOP control mechanisms, also referred to herein as ocularwall tension control mechanisms. This is because ocular wall tension isproportionally related to, and determined in part, by intraocularpressure. Other factors that may effect wall tension are scleralthickness and rigidity, which can be variable due to patient age,gender, and individual variations.

The IOP mechanisms may control IOP during the placement and positioningof the device tip at the target location on the ocular surface, and/orintraocular or intravitreal positioning of the dispensing member(conduit) during intraocular or intravitreal injection of a drug. Forexample, the IOP mechanisms may control IOP prior to and during theintraocular or intravitreal positioning of a dispensing member beingused for trans-scleral or trans-corneal penetration. Once penetration ofthe ocular surface by the dispensing member occurs, IOP will typicallydecrease. This decrease in IOP may occur immediately after penetrationof the ocular surface by the dispensing member.

In some variations, the IOP control mechanisms allow (enable) thedevices to generate an IOP between 15 and 120 mm Hg during the placementand positioning of the device tip at a target location on the ocularsurface, and/or intraocular positioning of the dispensing member. Inother variations, the IOP control mechanisms allow (enable) the devicesto generate an IOP between 20 and 90 mm Hg during the placement andpositioning of the device tip at a target location on the ocularsurface, and/or intraocular positioning of the dispensing member. In yetfurther variations, the IOP control mechanisms allow (enable) thedevices to generate an IOP between 25 and 60 mm Hg during the placementand positioning of the device tip at a target location on the ocularsurface, and/or intraocular positioning of the dispensing member.

The IOP control mechanisms may also allow (enable) the devices tomaintain the IOP between 10 and 120 mm Hg, or between 15 and 90 mm Hg,or between 20 and 60 mmHg during any duration of time of the intraocularinjection procedure. In some variations, the drug injection rate isslowed or completely aborted by the device if the intraocular pressureexceeds a certain predetermined value, for example 120 mm Hg, or 60 mmHg, or 40 mm Hg. Here the IOP control mechanism may be configured todetect a IOP level during the intraocular drug injection of, e.g., 90mmHg, or 60 mm Hg, or 40 mm Hg.

The IOP control mechanism may include a spring, or it may comprise amechanical or an electrical control mechanism. In general, the IOPcontrol mechanism will be configured to balance the frictional forces ofthe injection plunger and fluid injection resistance pressure (forcerequired to push fluid through the needle into the pressurized eyefluids). The IOP control mechanisms may be coupled to the device housingand actuation mechanism in a manner that allows automatic adjustment ofthe force of dispensing member deployment and plunger advancement. Thatis, the IOP control mechanism may be configured to affect apredetermined level of force of the dispensing member and apredetermined intraocular pressure level. Again, use of the IOP controlmechanisms may generate higher than the resting IOP prior to dispensingmember deployment so that scleral elasticity and the potential fordevice backlash is decreased, and to facilitate scleral penetration bythe dispensing member.

In one variation, the IOP control mechanism is a pressure relief valvethat bypasses the injection stream once a maximum pressure is reached.In another variation, the IOP mechanism is a pressure accumulator thatdampens the IOP within a specified range. Some variations of the IOPcontrol mechanism may include a pressure sensor. In yet anothervariation, the IOP control mechanism includes a slidable cap or shieldthat covers the dispensing member prior to its deployment, but which mayslide or retract along the surface of the device housing to expose,deploy, or advance the dispensing member e.g., upon attainment of apredetermined IOP level. Sliding of the cap may be manually adjustable,e.g., using a dial, or automatically adjustable, step-wise, orincremental in nature. For example, as shown in FIG. 40, integratedinjection device (500) includes, among other elements, a cap (502), astop (504), a trigger (506), a spring (508), a plunger (510), a seal(512), a drug reservoir (514), a needle (516), and a syringe (518). Inuse, when cap (502) is placed against the ocular surface and pressureapplied against the ocular surface, cap (502) slidably retractsproximally (in the direction of the arrow) to stop (504) as the syringe(518) and needle (516) are advanced. The trigger (506), e.g., a lever,may then be depressed to release spring (508), which advances plunger(510) and seal (512) to inject drug from the drug reservoir (514)through needle (516). Once the drug is injected, cap (502) slides backover the needle (516).

A locking mechanism may also be used to prevent sliding of the cap,cover or ocular contact surface, or prevent deployment of the dispensingmember until a predetermined IOP is reached. The locking mechanism mayalso be used to prevent sliding of the cap, cover, or ocular contactsurface if a predetermined IOP is not reached. For instance, the lockingmechanisms included on the devices described here that include aslidable cover, cap, etc., may be released manually or automaticallywhen the IOP reaches a predetermined level, such as between 20 mm Hg and80 mm Hg. Such locking mechanisms may include without limitation, hightraction surfaces, locking pins, interlocking raised ridges, or anyother type of locking mechanism that prevents the tip of the device,e.g., the cap or cover of the device, from sliding and thus exposing theneedle.

In yet further variations, the IOP control mechanism includes ahigh-traction surface or raised ridges on the cap, cover, shield, orocular contact surface situated over the dispensing member. Suchfeatures may be disposed on the inner surface of the cap, cover, shield,or ocular contact surface and configured so that upon sliding in theproximal direction, the high-traction surface or raised ridges mate withcorresponding structures (e.g., crimps, dimples, protrusions, otherraised ridges) on the surface of the device housing or other appropriatedevice component to provide resistance of the cap, cover, shield, orocular contact surface against the eye wall (thus increasing ocular walltension and IOP). In this instance, the IOP control mechanism comprisesa resistance component, as further described below. As stated above, thecap, cover, shield, or ocular contact surface may be configured so thatsliding is manually or automatically adjustable, step-wise, orincremental in nature. When raised ridges are employed, any suitablenumber may be used, and they may be of any suitable size, shape, andgeometry. For example, the raised ridges may be circumferentiallydisposed within the cap, cover, or ocular contact surface. In someinstances, the raised ridges are configured with surfaces of differingslope. For example, the distal surface may be configured to be steeperthan the proximal surface. With this design, incremental sliding andincremental increases in IOP may be generated when the cap, cover,shield, or ocular contact surface is slid proximally, but sliding of thecap, cover, shield, or ocular contact surface back over the dispensingmember may also be accomplished due to the decreased slope of theproximal ridge surface.

IOP control mechanisms that provide resistance may slide and expose aneedle secured to the housing, e.g., a syringe, when the force exertedon the shield is transmitted onto the eye wall. The exerted force maycreate an intraocular pressure of between about 10 mmHg to about 150 mmHg, between about 12 mm Hg and about 120 mm Hg, between about 15 mm Hgand about 60 mm Hg, or between about 15 mm Hg and about 40 mm Hg.

Resistance Component

The application of pressure to the surface of the eye may beaccomplished and further refined by including a resistance component,e.g., a dynamic resistance component to the injection device. Thedynamic resistance component may be configured to detach from theinjection device. The dynamic resistance component may include aslidable element and/or a fully rotatable (e.g., rotate 360 degrees) orpartially rotatable (e.g., rotate less than 360 degrees) element coupledto the housing. The dynamic resistance component may be configured sothat it can be fully or partially rotated about the long axis of thedevice using only one finger (e.g., the middle finger) while holding thedevice with the thumb and the index finger of the same hand. In somevariations, the slidable element comprises a dynamic sleeve configuredto adjust the amount of pressure applied to the eye surface, as furtherdescribed below. As previously stated, certain variations of the ocularwall tension control mechanism function as dynamic resistancecomponents. A force between about 5 gm to about 100 gm or about 10 gm toabout 30 gm may be needed to initiate movement of the slidable elementsagainst resistance that is generated by the slidable elements. In somevariations, it may take about 20 gm to about 25 gm of force to initiatemovement of the slidable elements. In other variations, it may takeabout 3 gm to about 30 gm of force to initiate movement of the slidableresistance component.

The dynamic resistance component may also be configured as a dynamicsleeve. Similar to the slidable cap previously described, the dynamicsleeve may be configured to increase intraocular pressure and tension ofthe eye wall prior to needle injection. However, the dynamic sleeve iscapable of being manually manipulated to thereby adjust the amount ofpressure applied on surface of the eye (and thus, the amount of eye walltension). Having the ability to manually adjust the applied pressure mayallow the injector (user) to have improved control of the injection siteplacement and the injection angle, and also enhances the user's abilityto stably position the device on the ocular surface prior to needledeployment. In general, the dynamic sleeve is designed to enable theuser to precisely position the device tip at the targeted site on theeye surface and to firmly press the device tip against the eye wall toincrease wall tension and intraocular pressure. The dynamic sleeve maybe used to raise intraocular pressure to a predetermined level, asdescribed above, prior to the initiation of sleeve movement and needledeployment. It should be understood that the terms “dynamic sleeve,”“sleeve,” “slidable sleeve,” “dynamic sleeve resistance controlmechanism,” and “sleeve resistance mechanism” are used interchangeablythroughout. In some variations, the dynamic sleeve is removable ordetachable from the drug conduit, rendering the drug conduit completelyuncovered. In other variations, the dynamic sleeve is fixedly attachedto the drug conduit and at least partially covers the conduit. In yetfurther variations, the dynamic sleeve may be rigid or non-deformable.The dynamic sleeve may be configured such that when a pulling force(e.g., retraction away from the eye) is exerted on the sleeve, thismovement may facilitate needle exposure and reduce the amount ofpressure force (down to 0 Newton) (“N” refers to the unit of force“Newton”) needed to be applied to the eye wall in order to slide thesleeve back and expose the needle. The dynamic sleeve may also beconfigured such that when a pushing force (e.g., advancement) is exertedon the sleeve, this movement may counteract and impede needle exposure,which may allow the device tip to apply increased pressure to the eyewall prior to the initiation of sleeve movement and needle exposure.

Some variations of the dynamic sleeve provide a variable force thatfollows a U-shaped curve, as described further in Example 1 and FIG. 46.Here the highest resistance is encountered at the beginning and the endof dynamic sleeve movement along the housing with decreased resistancebetween the start and end points of dynamic sleeve travel. In use, thistranslates to having an initial high-resistance phase (upon initialplacement on the eye wall) followed by a decrease in resistance tosleeve movement during needle advancement into the eye cavity. When theneedle is fully deployed, the dynamic sleeve will typically be at theend of its travel path, and increased resistance would again beencountered. This increase in resistive force allows the sleeve to cometo a smooth, gradual stop (instead of an abrupt hard stop at the endpoint) to minimize the risk of transmitting damaging amounts of force tothe inert eye wall (which in turn minimizes the risk of causingdiscomfort or injury to the eye). Here an exemplary dynamic sleeve maybe configured to be tapered at the proximal end and distal end.Referring to the sectional view in FIG. 42, integrated injection device(42) includes a housing (44), a resistance band (46) wholly or partiallysurrounding the housing, and a dynamic sleeve (48) that can be slidablyadvanced and retracted upon the housing (44). When partially surroundingthe housing, the resistance band may be referred to as a resistancestrip. The dynamic sleeve (48) has a proximal end (50) and a distal end(not shown) that are tapered. The tapered ends may provide highertraction at the beginning and the end of the dynamic sleeve travel pathalong the device housing (44) (that is at the beginning and end ofneedle deployment). The taper at the proximal end (50) provides highertraction and resistance at the beginning of dynamic sleeve movement whenit contacts resistance band (46). The thickness of the resistance band(46) may be varied to adjust the amount of resistance desired. Forexample, the thickness of the resistance band may range from about 0.01mm to about 5 mm, or range from about 0.1 mm to about 1 mm.Specifically, the thickness of the resistance band may be about 0.05 mm,about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm,about 0.6 mm, about 0.7 mm, about 0.75 mm, about 0.8 mm, about 0.9 mm,about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0 mm,about 3.5 mm, about 4.0 mm, about 4.5 mm, or about 5.0 mm. The width ofthe resistance band may also vary and be about 1.0 mm, about 1.5 mm,about 2.0 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm,about 4.5 mm, or about 5.0 mm. Upon reaching the wider middle segment(52), lower-traction and lower resistance movement is encountered,followed by higher traction and higher resistance at the end of needledeployment as the taper at the distal end of the dynamic sleeve isreached. As the dynamic sleeve becomes progressively more tapered at thedistal end, more traction is produced against the device housing untilit gradually comes to a complete stop. Instead of both ends beingtapered, in some variations one of the proximal end and distal end ofthe dynamic sleeve may be tapered.

Variable traction force may also be provided by components such ascircular raised bands or ridges on the outside surface of the devicetip. These components may provide counter-traction when approximatedagainst another circular raised band or ridge on the inside surface ofthe movable dynamic sleeve (inner bands or ridges). When the outer andinner bands or ridges are in contact with each other before the dynamicsleeve begins to move, they generate high traction and high resistanceto dynamic sleeve movement. Once the dynamic sleeve starts to move, theraised band on the outside of the device housing moves past the raisedband on the inside of the dynamic sleeve, which may result in a rapiddecrease in resistance to dynamic sleeve movement and, therefore,decreased pressure on the eye wall by the device tip. The shape of theraised interlocking bands or ridges will generally determine the shapeof resistance decrease. For example, the resistance decrease may followa sine-shaped profile.

The resistance component may also be configured as a slidable shieldthat is coaxial with housing, and which has a lumen and an internalsurface that forms a raised step or platform about at least a portionthereof. In some variations, the step or platform circumscribes theentire lumen of the slidable shield. The luminal diameter of theslidable shield is generally reduced in the area of the step or platformto thus provide higher friction (resistance) when the shield slidesalong the housing. Thus, the internal diameter of the slidable shieldmay typically be smaller in its distal portion than in its proximalportion. The width of the raised step or platform may be from about 0.1mm to about 5 mm, or from about 0.5 mm to about 2 mm. The raised step orplatform may also have at least one rounded or sloped edge, e.g., eitherthe proximal or distal edge, or both edges. The raised step or platformmay further include an edge that is gradually sloped to achieve agradually increase the diameter of the lumen and generate a smoothreduction in friction as the slidable shield moves to expose the needle.For example, the edge can be sloped so that the lumen is greater in theproximal portion of the shield than at its distal portion.

In another variation, the dynamic sleeve may generate a force thatcontinuously decreases from its highest point before needle deployment(when the dynamic sleeve completely covers the needle), to its lowestpoint when the dynamic sleeve begins to move to expose the needle tip.Here the force remains low until the end of dynamic sleeve travel andcomplete needle deployment. This pattern of resistance decrease mayfollow a sine-shaped curve.

Slidable advancement of the dynamic sleeve may generate a resistanceforce against its movement ranging from 0 N to about 2 N. In someinstances, slidable advancement of the dynamic sleeve generates a forceranging from about 0.1 N to about 1 N. As previously stated, the amountof force that may be required to move the sleeve may range between about3 gm and about 30 gm.

The resistance component may be configured to be part of an injectorattachment or injector assembly that can be removably attached to anysuitable syringe, including syringes of the luer lock and luer sliptype. The resistance component of the injector attachment may interfacewith the internal surface, external surface, or both surfaces of aslidable sleeve. In some variations, the injector attachment comprises aring or disc-shaped component that at least partially surrounds theexterior of, and is raised above the surface of the injector attachment.The ring may function as a backstop for the slidable resistancecomponent and/or as a grip or handle to help manipulate the injectorattachment on and off the syringe. As shown in FIGS. 57A and 57B, thering (1904) may entirely surround the injector attachment (1900) and bedisposed along the axial length of the injector attachment (1900) aboutone-tenth to about one-half, or about one-eighth to about one-third, ofthe distance between the proximal end (1906) of the injector attachment(1900) and the proximal end (1908) of the projections (which aredescribed in more detail below).

In some instances, the resistance component may include a plurality ofappendages attached to, or formed as part of, the needle hub. Here thedevice may be generally configured to include an injector attachmentthat can be exchanged for the loading needle of a typical syringe. Theinjector attachment may include a sterile injection needle (e.g., a 30to 33 gauge needle) and a resistance component (e.g., a dynamic sleeve).An advantage of this modular design may be that side-loading of druginto the device drug reservoir is no longer needed because the devicecan be loaded like a regular syringe. Such a modular assembly maycontain a universal female connector comprising, e.g., a flange, at theproximal portion of the attachment. The female connector may enable theinjector attachment to removably interface (i.e., attach and detach)with a male luer-tip drug reservoir. The drug reservoir may be a syringethat includes a luer fitting of the luer lock or luer slipconfiguration, or any derivative or modification of the luer tip. Themodular design may enable loading of a drug reservoir within any of thedevices described herein with a drug from a container, e.g., a drugvial. A loading needle can first be used to transfer the drug from thevial to the reservoir. The loading needle may then be detached orswitched for an injector attachment.

For example, as shown in FIG. 53, an exemplary injector attachment(1500) is shown. Injector attachment (1500) comprises a needle hub(1502) for removably coupling the attachment (1500) to a syringe (notshown). The needle hub (1502) is configured to include a plurality ofprojections (1504) that extend distally from the needle hub. Althoughfour projections are shown in the figure, any suitable number ofprojections may be employed on the needle hub. For example, twoprojections, three projections, four projections, five projections, orsix projections may be employed. The projections may be made from anysuitable material. In some variations, the projections are formed from apolymeric material, e.g., a plastic material. In one variation, theprojections are made from polypropylene. The projections may also beradially spaced about the periphery of the hub in any suitable manner.For example, the projections may be equally or unequally spaced, orsymmetrically or asymmetrically spaced, about the periphery of the hub.A slidable shield (1506) may at least surround the needle hub (1502) andprojections (1504), and may be operatively coupled to an ocular contactsurface having a measuring component (1508). The projections typicallyprovide friction (resistance) with the internal surface of the slidableshield. The desired resistive force that may need to be overcome inorder to advance the resistance component (e.g., the slidable shield)may vary between about 0.1 grams and about 100 grams, or between about5.0 grams to about 30 grams. An exemplary resistance profile is shown inFIG. 59. It is understood that other friction profiles are alsocontemplated that may require the application of constant force,increasing force, etc., if desired. The amount of friction could beadjusted or optimized, e.g., by increasing the contact surface of theprojections, narrowing the internal diameter of the slidable shieldlumen, or by varying the materials comprising the contact surfaces(e.g., to vary the coefficient of friction and stiffness). In somevariations, there is an interference fit between the slidable shield andthe projections. In some instances the interference fit may range frombetween about 0.05 mm (about 0.002 inches) to about 1.0 mm (about 0.04inches), or from about 0.08 mm (about 0.003 inches) to about 0.76 mm(about 0.03 inches). For example, an interference fit of about 0.13 mm(about 0.005 inches) between the inner surface (inside diameter) of theslidable shield and the outer diameter of the needle hub assembly mayyield a range of force from about 3 grams to about 30 grams of resistiveforce. In general, a 2% to 5% interference may provide an appropriateamount of resistance. Further, the softer (i.e., less rigid) theprojections, the greater the interference. Either or both contactsurfaces may also be lubricated, coated, or siliconized to facilitatethe smooth sliding movement of the surfaces, if desired. In onevariation, a smooth mobility element, e.g., a silicone or thermoplasticelastomeric (TPE) washer, may be placed inside the shield to generatesmooth sliding with the drug conduit or the internal surface of thelumen of the shield, or a coating (e.g., a fluoropolymer coating) or alubricant applied to at least one friction/traction surface.

However, not all the projections (1504) may be used to provideresistance to shield (1506) movement. Any number of the projections(1504) included may be used to provide resistance. For example, just oneor two projections out of four may be used to provide resistance.Projections not used to provide resistance may provide forward andrearward sliding limits for the shield, and may also prevent the shieldfrom rotating relative to the syringe axis. Needle (1514) is attached tothe hub (1502) and extends distally therefrom. The force and resistancecurves, decreases in resistance, and the amount of force generatedbetween the projections and the slidable shield may be the same orsimilar to that described for the dynamic sleeve.

One or more longitudinal grooves may also be placed on the internalsurface of the slidable sleeve. The grooves may extend through either apartial-thickness or a full-thickness of the sleeve's wall. Thus, theprojections from the hub (or needle assembly or housing) travel withinthe grooves to prevent the sleeve from spinning/rotating around its longaxis. In one variation, the grooves preventing the rotation of thesleeve may be useful when the measuring component covers the 360 degreesof circumference of the tip (i.e., when there is no need to rotate thesleeve to orient the measuring component towards the limbus).

The injector attachments may be made by bonding the needle to a needlehub configured with a plurality of projections. A shield such as the oneshown in FIGS. 54B and 54C may be slid over the needle hub until itsnaps in place. No adhesives are used to secure the shield to the needlehub. A safety clip (as further described below) may be attached to theneedle hub to prevent back and forward movement of the shield on theneedle hub. The needle hub may be made from any suitable material. Insome variations, the needle hub is made from polypropylene. In othervariations, the needle hub is made from polycarbonate. The slidableshield may also be made from any suitable material. For example, theslidable shield may be made from a polycarbonate, including polishedpolycarbonate.

Some variations of the safety clip generate resistance that impedes themovement of the shield relative to the drug conduit. For example, theclip could lock the shield in a certain position or more than oneposition (such as pre-deployment resting position, post-injection endposition, or both), and may prevent the movement of the shield relativeto the drug conduit. In one variation, the safety clip does not rotaterelative to the long axis of the device. In another example, the safetyclip may be rotatable relative to the long axis of the device.

Another variation of the injector attachment is shown in FIGS. 54A-54C.In these figures, the injection device (1600) is depicted as comprisinga syringe body (1602) having a proximal end (1604) and a distal end(1606). An injector attachment (1608) is removably coupled to the distalend (1606). In this variation, and as illustrated in more detail inFIGS. 54B and 54C, injector attachment (1608) includes a needle hub(1610) having a proximal end (1611), a needle (1612), and fourprojections (1614) extending distally. As previously stated, anysuitable number of projections may be used. The projections (1614) maybe configured, shaped, etc. at their distal ends with a tab (1616).Instead of tabs, the distal ends may also be configured as hooks, flaps,etc. Injector attachment (1608) also includes a slidable shield (1618)having a proximal end (1620) and a distal end (1622), and slots (1624)provided through the wall, or partially through the wall, of the shield(1618). The slots may have any suitable size, shape, and geometry, andwill typically be configured to interface with the slots in acomplimentary manner. The projections (1614) generally have a slightinterference fit with the inside surface of the slidable shield (1618).An ocular contact surface having a measuring component (1626) may becoupled to the distal end (1622) of the shield (1618). In use, theprojections (1614) slide along the inside surface of the slidable shield(1618), and because of the interference fit with the inside surface,provide resistance to shield (1618) movement. Resistance is provideduntil the projections (1614) reach the slots (1624) in the shield(1618). Upon reaching the slots (1624), the tabs (1616) at the distalends of the projections (1614) expand (e.g., radially expand) into theslots (1624), thereby decreasing the resistance to movement of theshield (1618). The amount of resistance can be adjusted by adjustingsuch factors as the thickness of the tabs or the degree of interferenceof the projections with the inside surface of the shield.

A clip (1607) may be provided on the needle hub (1610) for preventingaxial movement of the shield (1618) along the outer surface of theneedle hub (1610). Axial movement of the shield (1618) can occur whenthe clip (1607) is removed. The clip may be a safety feature thatprevents the resistance component, e.g., the slidable shield fromlongitudinally moving along the axis of the device. The clip may be ofany suitable configuration that prevents axial movement of the shieldwhen coupled to the needle hub, and which allows axial movement whenremoved from the needle hub. In some variations, the clip may be lockedto the device housing or the needle hub assembly so that it does notrotate about the housing (e.g., about the longitudinal axis of thedevice). However, in other variations, the clip may be configured to berotatable about the housing. In some variations, as further describedbelow, a locking mechanism, such as a clip, that controls the mobilityof the dynamic shield or sleeve is non-removably attached to the deviceshousing, the shield, needle hub/assembly, drug reservoir, or any part ofthe device. For example, the locking mechanism may be released bypressing its rear lever, thus releasing the slidable shield andrendering it mobile.

Although the clip is shown as comprising a looped body portion and tabsin the figures, it may be of any suitable configuration. For example,the body portion may have a width between about 1 mm and about 12 mm,between about 3 mm and about 10 mm, or between about 4 mm and about 8mm. The clip may be made from any suitable material. Exemplary materialsinclude without limitation, polyethylene, polycarbonate, polypropylene,acrylonitrile butadiene styrene polymers, Delrin® acetal homopolymers,polyurethane, acrylic polymers, polyether ether ketone, and combinationsthereof. In one variation, the clip is made from polyethylene.

Clips or levers that are fixed or non-removably attached to a portion ofthe injector device or injector attachment could also be employed. Theseclips or levers could be of any suitable configuration that preventsmovement of the resistance component. Some variations of the clip orlever may be fixed to the device housing, while others may be fixed to aportion of the needle assembly. For example, as shown in FIG. 63A, thelever (6002) may be attached to the needle assembly (6004) of the device(6000). The lever may have a locked configuration or position (e.g., a“down position” or “down-locked position” that renders the slidableshield immobile) and an unlocked configuration or position (e.g., an “upposition” or “up-locked position” that render the slidable shield mobilealong the needle's long axis), or, for example, a combination of both anup-locked and a down-locked positions. The lever (6002) comprises twoends, where one end includes a release tab (6006) and the other end, alocking shoulder or lever-actuation tab (6008), which may for example belocated at the front end of the lever. In one variation, a lockingmechanism is located on one end of the lever (e.g. either front or rearend). In another variation, a locking mechanism is located on both endsof the lever. In yet another variation, a locking mechanism is locatedalong the lever between its front and rear end.

In one variation, the lever-actuation tab is a release tab that releasesthe locking action of the lever when a pressure force is applied to thetab rendering the slidable shield covering the needle mobile. In anothervariation, the lever-actuation tab is a locking tab that locks theslidable shield when a pressure force is applied to the tab renderingthe slidable shield covering the needle immobile. In one variation, thelever-actuation tab is located on one end of the lever (e.g. eitherfront or rear end of the lever). In another variation, thelever-actuation tab is located on both ends of the lever. In its lockedposition (FIG. 63B), the locking shoulder (6008) contacts a portion ofthe resistance mechanism, here shown as slidable sleeve (6010) toprevent movement of the slidable sleeve (6010). When the release tab(6006) is depressed, e.g., in the direction of arrow A, as shown inFIGS. 63C-63D, the pressure on the release tab (6006) pivots the lever(6002) at its point of fixation to the needle assembly (6004) so thatthe end with the locking shoulder (6008) is lifted, e.g., in thedirection of arrow B. By lifting the locking shoulder (6008), contactbetween the locking shoulder (6008) and slidable sleeve (6010) isremoved, and the slidable sleeve (6010) is unlocked and free to move(i.e., slide) proximally. After injection has been completed, theslidable sleeve (6010) can again be locked against movement by pressingthe locking shoulder (6008) so that it contacts the slidable sleeve(6010).

In one variation, the lever may have a built-in bias toward theshield-immobilizing position. In one example, when no external pressureforce is applied to the lever's release tab, the lever exerts a certainresistance on the slidable shield, which prevents the shield from movingbackward and exposing the needle tip.

In another variation, the lever may have two equal positions without anybias, one shield-immobilizing position and the other shield-mobilizingposition. For example when the release end (e.g. the rear end) of leveris depressed, the lever unlocks the slidable shield's anterior-posteriormovement (i.e. mobilizes the shield) and the shield remains mobilizeduntil external pressure is applied to the front end of the lever (e.g.the front end of the lever may be manually depressed or the rear end ofthe lever may be lifted), thus the lever exerts no built-in bias foreither shield-immobilizing or shield-mobilizing position.

In yet another variation, the lever may have a built-in bias toward theshield-mobilizing position, such as when no external pressure force isapplied to the lever, the lever exerts no resistance on the slidableshield rendering it freely mobile in anterior-posterior direction unlessan external pressure force is applied to the lever, which locks theslidable shield rendering it immobile but only while the externalpressure force is being applied to the lever.

In one variation, the lever or clip may permanently lock the slidableshield rendering it permanently immobile at the end of the injectionprocedure reducing the risk of an accidental needle stick andfacilitating safe disposal of the device. This may be achieved, forexample, by applying an external pressure force to the front end of thelever or twisting the slidable shield around its long axis in order tolock the front tip of the lever to the slidable shield through, forexample, a slot, groove or a hole in the slidable shield rendering theslidable shield immobile in the anterior-posterior direction.

In one variation, the lever may have a combination of the built-in biasand at least one or two lever-locked positions. For example, alocked-down position may increase resistance to sliding movement orcompletely immobilizes the slidable shield. In another example, alocked-up position may decrease resistance to sliding movement orcompletely mobilizes the slidable shield rendering it freely mobilealong the needle's long axis. The above lever-locked positions may bemaintained when there is no external pressure force applied onto thelever.

The lever may comprise a lever-positioning mechanism, for example aflexible arm connector (FAC) (7000), as shown in FIG. 65), that mayconnect the lever (7002) to the device housing (7004). The FAC (7000)may be useful in maintaining a certain lever position and angle, forexample a down- or up-bias. The lever-positioning mechanism may alsomaintain the lever in a certain position when no pressure force isapplied onto the lever. The lever-positioning mechanism may enable thepositional bias of the lever (e.g., down- or up-position bias).

The FAC may also provide resistance to bending and positional memoryenabling a certain pre-determined positional bias of the lever (7002).For example, the FAC (7000) may return the lever (7002) into itsshield-locking position when there is no external force applied onto thelever, thus re-locking and/or immobilizing the slidable shield (7006).

The FAC (7000) may also control and/or regulate the amount of forcerequired to unlock the resistance component, e.g., slidable shield(7006). In one variation, a FAC may regulate the slidable shield'ssliding movement by gradually increasing or decreasing the resistanceagainst the shield's movement, for example if the lever is onlypartially engaged with the shield providing partial resistance toshield's sliding movement, e.g., through an interference fit. Thus, thelever may comprise or be part of the “resistance component,” describedelsewhere herein.

As further illustrated in FIG. 65, the FAC (7000) may comprise a lockingelement (7008), to enable the locking of the lever in the up position,which renders the slidable shield mobile. The lever may also comprise asecond locking element (7010) (resulting in a bi-locking FAC or lever)that enables the locking of the lever in the down-position (i.e.,immobilizing the slidable shield). Thus, in some variations the lockingFAC comprises at least one or two locking elements (e.g., an up-lockingand a down-locking element) and its flexible arm providing a down-biasfor the lever when it's unlocked.

The clip or lever may comprise a resistance component, a safety feature,or a combination thereof that prevents the resistance component, e.g.,the slidable component such as a shield or sleeve from longitudinallymoving along the axis of the device. For example, the clip may preventthe slidable component from moving relative to the drug conduit in thepre-deployment or resting state. In some variations, the clip mayprevent the slidable component from moving relative to the drug conduitin both pre-deployment and post-injection states when the tip of thedrug conduit, for example an injection needle, is completely covered bythe slidable component such as a shield or a sleeve. In some variations,the clip may create resistance to and partially or completely hamper theback and forth mobility of the slidable component relative to the drugconduit in at least one or both pre-deployment and post-injection stateswhen the tip of the drug conduit is completely covered.

The eye is a unique organ in that it is shaped as a hollow sphere thathas certain intraocular pressure (IOP) normally maintained within acertain range that increases when external pressure is applied onto theeye wall and may cause tissue damage or intraocular arterial and/orvenous occlusions. In addition, the eye is exquisitely sensitive toexternal pressure that may cause substantial discomfort for theindividual in the form of photopsia, uncomfortable pressure sensationand/or pain, which may be difficult to completely abolish even bytopical anesthesia. Thus, there is a need for a mobility controlmechanism that controls the mobility of a slidable component thatprotects the tip of a drug conduit, such as the injection needle, whilethe device is placed onto the eye wall, while controlling the level ofpressure applied onto the eye wall. Such a mechanism enables stable andsafe placement of the intraocular drug delivery device onto the eyesurface while the slidable component is locked and non-mobile in theneedle pre-deployment state, but without applying excessive pressureonto the eye wall. The mechanism may be gradually or completely releasedto partially or completely remove the lock on the slidable componentrendering it partially or freely mobile in the needle deployment stateduring intraocular injection. Thus, the mobility control mechanismenables manual control of the slidable element's mobility ranging fromit being completely locked and immobile to being partially mobile withcertain resistance, to being completely and freely mobile relative tothe drug conduit. For example, the slidable component may be non-mobilein the pre-deployment and post-injection states but freely or partiallymobile during the injection state by completely or partially releasingthe mobility control mechanism, for example by manually pressing on therear lever of the control mechanism thus lifting its front locking part.The mobility control mechanism ensures that the drug conduit, such as aninjection needle, is not deployed or exposed prematurely before thedevice is properly positioned in the desired location of the eyesurface. In other variations, it may also ensure that the slidableshield or sleeve securely covers the tip of the drug conduit at the endof the injection procedure preventing accidental needle sticks.

In some instances, the proximal end of the slidable shield comprises acentration/stabilization element, such as a band or ring having acertain thickness and its internal lumen diameter smaller than theremainder of the proximal portion of the slidable shield. Thecentration/stabilization enables a snug interface between the slidableshield and the needle hub assembly or device housing, thus stabilizingand centering the slidable shield relative to the long axis of thedevice during its travel. In one example, the centration/stabilizationelement is attached to the internal surface of the proximal end of theslidable shield. The slidable shield may have slots provided through thewall, or partially through the wall, of the shield. The slots may haveany suitable size, shape, and geometry, and will typically be configuredto interface with the slots in a complimentary manner.

In yet a further variation, as shown in FIG. 61, the resistancecomponent of the injector attachment (4000) may be configured as aslidable shield (4002) that has a wider proximal portion (4004) and anarrower distal portion (4006). Here the internal diameter of the lumenof the wider portion of the slidable shield is generally larger than theinternal diameter of the narrower portion. This configuration may allowthe wider portion (4004) to be the portion where friction/tractionelements of the shield (4002) and needle hub assembly interface (4008)(or of the shield and housing in other variations), and the narrowerportion to be the portion that enables the attachment of a measuringcomponent (4010) onto the device tip.

In some instances, the internal diameter of the narrower portion of theslidable shield may be substantially similar to the external diameter ofa needle holder (4012) (e.g., see FIG. 61). The needle holder that maybe attached to the needle hub assembly may fit snugly into the lumen ofthe narrow portion of the shield at least along some part of the travelpath of the shield, which may enable stabilization and centration of thedrug conduit attached to the needle holder. In these variations, theclearing between the external surface of the needle holder and theinternal surface of the lumen of the narrow portion of the shield may bebetween about 0.01 mm and about 1 mm.

Alternatively, resistance or friction force may be generated by thefriction between the drug conduit (e.g., a needle) and the conduit'stunnel (e.g, needle tunnel), device tip, or ocular contact surface. Forexample, the resistance or friction force may be generated between theshaft of the drug conduit and the material comprising the device tipand/or ocular contact surface.

In one variation, the resistance component comprises a combination of anexternal resistance component (e.g., a resistance lever that releaseablyimmobilizes a slidable shield described herein) and an internalresistance component (e.g., friction between the drug conduit and itstunnel or between the needle hub assembly and the slidable shield).

As further shown in FIG. 61A, the removable injector attachment mayinclude a clip (4016) that is capable of being removed from the needleassembly (4014), and a filter (4018), which here is a hydrophilicfilter. In other variations, the removable injector attachment includesboth a hydrophilic filter (4018) and an air removal mechanism (4020),which here is a hydrophobic filter.

As previously stated, the benefit of the injector attachment is that itcan be used with commercially available syringes, e.g., tuberculin orinsulin syringes. Drug may first be loaded into the syringe in the usualmanner using a standard loading needle instead of through a side port.The standard needle may then be removed and an injector attachment, asdescribed herein, placed on the luer slip at the distal end of thesyringe. The clip may then be removed to free the shield and allow it toaxially move along the surface of the needle hub. The ocular contactsurface (e.g., with measuring component) may then be placed on thesurface of the eye. Next, the syringe body may be advanced to advancethe needle into the eye. During this syringe advancement step, theprojections on the needle hub generally slide within the shield distally(toward the ocular contact surface). The shield may also slideproximally (toward the proximal end of the needle hub) due to theinitial wall tension of the ocular surface. The resistance to sliding ofboth the needle hub and shield may be adjusted or manipulated based onthe particular structure or configuration of the projections extendingfrom the shield. The needle is prevented from being advanced any furtheronce the tabs on the distal ends of the projections snap into the slotsin the wall of the shield. The needle may be advanced from between about1 mm to about 25 mm, or from between about 2 mm to about 8 mm, into theeye before the slots are reached. Drug may then be injected into the eyeusing the plunger of the syringe and then the syringe and needle removedfrom the eye.

In variations where the resistance component comprises a slidableshield/sleeve, the resistance component may function to protect thesterility of the drug conduit, e.g., a needle. The slidable shield mayprotect needle sterility by protecting it from accidental contact withand contamination from, the eyelids, eyelashes, ocular surfacesecretions, and/or airborne pathogens. The slidable shield/sleeve mayalso function to protect the needle from contamination by the eyelidsand lashes when the patient blinks. Further, the slidable shield/sleevemay function to prevent or minimize the circulation of non-sterilesecretions and tears over the injection site.

Measuring Components

The devices described here may include a measuring component that may beuseful in determining the location of the intraocular injection site onthe eye surface. Some variations of the device may include an ocularcontact surface having a high-traction surface integrated with ameasuring component. The measuring component may be fixedly attached orremovably attached to the ocular contact surface. The measuringcomponent may also be configured to fully (360 degrees) or partiallyrotate (less then 360 degrees) about the long axis of the devicehousing. Inclusion of a rotatable (dynamic) measuring component mayallow the operator to maintain a comfortable grasp of the device withouthaving to change or reposition the finger placement pattern in order toappropriately orient the measuring component toward the limbus in anymeridian either in the left or right eye of a mammal (for exampleperpendicular to the limbus), in order to accurately determine theinjection site and before stably positioning the device tip on the eyesurface. A rotating (dynamic) measuring component may also enablesterile localization of injection site in any meridian/clock hourrelative to limbus circumference, while avoiding contact with theeyelids or eyelashes.

In some variations, the measuring component comprises one or a pluralityof measuring elements or tabs radially extending from the proximaldevice tip comprising an ocular contact surface. The radial measuringelements or tabs may be oriented perpendicular to the circumference ofthe proximal device tip comprising an ocular contact surface. In onevariation, the measuring component comprises, 1-12, or 3-9, or 6-8, or 6radially oriented measuring elements or tabs.

In one variation, the measuring component spans the entire circumferenceof the proximal device tip comprising an ocular interface surface. Inanother variation, the measuring component spans a portion of thecircumference of the proximal device tip comprising an ocular interfacesurface.

In one variation, the angle between any two adjacent radial elements isthe same and constant. In some examples, the angle between any twoadjacent radial elements is between 180 degrees and 15 degrees, orbetween 35 degrees and 25 degrees, or about 30 degrees.

In another variation, all radially oriented elements have equal lengths.In another example, at least some of the radially oriented elements havedifferent lengths. In one example, the lengths of the radially orientedelements vary between 1 mm-6 mm, or between 3.5 mm-4 mm.

As previously stated, the measuring component may be raised above theocular surface so that it prevents the eye lid from coming in contactwith the sterile ocular contact surface of the device tip (e.g., FIGS.2A-2B and 8). The specific configuration of the measuring component mayalso help to minimize the risk of inadvertent contamination of thesterile drug dispensing member (conduit) such as an injection needle.Such contamination may result from various causes such as the sterileneedle coming in inadvertent contact with an eyelid or other non-sterilesurface. The measuring components may also be colored in a manner toprovide color contrast against the surface of the eye including theconjunctiva, the sclera, and the iris. The distance from the deployedneedle tip to the tip of each individual measuring component may beabout 4 mm. Here the distance from the needle tip to the outer edge ofcorneo-scleral limbus may be about 3.5 mm. In some instances, e.g., whenthe measuring component comprises two tabs, and the tabs are rotated sothat the tips of the tabs are simultaneously touching the outer edge ofcorneo-scleral limbus, the injection site is located at 3.5 mm fromlimbus (ranging from 1 to 4 mm).

In general, the measuring component will enable the intraocularinjection site to be more precisely placed at a specific distance from,and posterior or anterior to, the corneal-scleral junction termed “thelimbus.” In some variations, the measuring component may provide forplacement of the intraocular injection site from about 1 mm to about 5mm, from about 2 mm to about 4.5 mm, or from about 3 mm to about 4 mm,from and posterior to the limbus. In another variation, the measuringcomponent may provide for placement of the intraocular injection sitefrom about 2 mm to about 5 mm posterior to the limbus, or about 3.5 mmposterior to the limbus. In other variations, the measuring componentmay provide for placement of the intraocular injection site from withinabout 3 mm or about 2 mm, from and anterior to, the limbus, or betweenabout 0.1 mm and about 2 mm from and anterior to the limbus. In onevariation, the measuring component provides for placement of theintraocular injection site between about 1 mm anterior to the limbus andabout 6 mm posterior to the limbus. In another variation, the measuringcomponent provides for placement of the intraocular injection sitebetween about 3 mm to about 4 mm posterior to the limbus.

The measuring components may have any suitable configuration. Forexample, the measuring components may be located on one side of theocular contact surface or on more than one side of the ocular contactsurface (e.g., FIGS. 9, 10, and 11). Here, when the tip of the measuringcomponent is placed right next to the corneo-scleral limbus, the site ofthe intraocular needle injection is placed at a particular distance fromthe limbus, e.g., between about 3 mm and about 4 mm posterior to thelimbus.

In alternative variations, the measuring component comprises one or moremembers (e.g., FIGS. 9, 10, and 11). These members may radially extendfrom the ocular contact surface. Having more than one member comprisethe measuring component may be beneficial in ensuring that the distancebetween the limbus and injection site is measured perpendicular to thelimbus and not tangentially as it may be the case when the measuringmeans comprise a single member. When the tips of one or more than oneradial member comprising the measuring component are aligned along thecorneo-scleral limbus, the site of the intraocular needle injection isplaced at a particular distance from the limbus, such as between about 3mm and about 4 mm posterior to the limbus.

More specifically, as shown in FIG. 8, the device tip having an ocularcontact surface comprises a measuring component (80) that enables thedetermination of the injection site at a certain distance relative tothe corneo-scleral limbus. As previously stated, in one variation themeasuring component is located on one side of the device tip. In anothervariation, more than one measuring component is located on more than oneside of the device tip. In yet further variations, the tip of themeasuring component may be raised, bent, etc., which prevents the eyelid from sliding over the measuring component and coming in accidentalcontact with the dispensing member (conduit) of device. Also in FIG. 8,the dispensing member (conduit) is shown as being completely shieldedinside the device tip.

FIG. 9 provides further detail about another variation of the measuringcomponent. Here the device tip comprises a ring-shaped ocular contactsurface (90) and a measuring component (91) that enables thedetermination of the injection site at a certain distance relative tothe corneo-scleral limbus. The outer circumference of the device tipthat comes into contact with the surface of the eye has, e.g., a ringshaped ocular interface, and the dispensing member such as an injectionneedle may be hidden inside and protected by the device tip. In FIG. 9,the measuring components (91) are located on one side of the device tip(FIGS. 9A-9B) or on more than one side of the device tip (FIG. 9C).Thus, when the tip of the measuring component is placed next to thecorneo-scleral limbus, the site of intraocular needle injection isplaced at a specific distance from the limbus, such as between about 3mm and about 4 mm posterior to the limbus. Any suitable number ofmeasuring components may be provided on the device tip, e.g., attachedto the ocular contact surface. When a plurality of measuring componentsare used, they may be arranged around the ocular contact surface in anysuitable fashion. For example, they may be circumferentially disposedaround the ocular contact surface or on one side of the ocular contactsurface. They may be equally or unequally spaced around thecircumference of the ocular surface. In other variations, the measuringcomponents may be symmetrically spaced or asymmetrically spaced aroundthe circumference of the ocular contact surface. These configurationsmay be beneficial in allowing the injector to rotate the device alongits long axis.

FIGS. 10A-10C provide additional views of measuring components that aresimilar to those shown in FIGS. 9A-9C. In FIG. 10, a ring-shaped ocularcontact surface (93) is shown having a measuring component (93) thatenables the determination of the injection site at a certain distancerelative to and perpendicular to the corneo-scleral limbus (94). Themeasuring components are depicted on one side of the device tip, or inanother variation, on more than one side of the device tip. Again, themeasuring components may comprise one or more members. Having more thanone member comprise the measuring component may be beneficial inensuring that the distance between the limbus and injection site ismeasured perpendicular to the limbus and not tangentially as it may bethe case when the measuring component comprise a single member. When thetips of all members comprising the measuring component are aligned alongthe corneo-scleral limbus, the site of the intraocular needle injectionis placed at a particular distance from the limbus, such as betweenabout 3 mm and about 4 mm posterior to the limbus.

More than one measuring component is also shown in FIGS. 11A-11D. Herethe measuring components (95) are depicted as extending from a commonattachment point (96) on the ocular contact surface. When the tips ofall members comprising the said measuring component are aligned alongthe corneo-scleral limbus, the site of the intraocular needle injectionis placed at a particular distance from the limbus, such as betweenabout 3 mm and about 4 mm posterior to the limbus.

Alternatively, the measuring components may be configured as one or moreflexible measuring strips. Flexible materials that may be used to makethe measuring strips include flexible polymers such as silicones. Asshown in FIG. 44A, the measuring strip (800) may extend from the devicetip (802), usually from the side of the ocular contact surface (804), sothat the distance between the limbus and injection site can be measuredperpendicular to the limbus. A positional indicator component (806) maybe employed to ensure that the measuring strip (800) is properly used.For example, as shown in FIG. 44B, correct positioning of the measuringstrip (800) (so that a 90 degree angle is formed between the measuringstrip and device housing (808)) may be determined when the positionalindicator component is substantially taut. In contrast, a slackpositional indicator component (as shown in FIG. 44C) would indicateincorrect positioning. The positional indicator component may be a cord.In one variation, the integrated device comprises at least threemeasuring strips. In another variation, the integrated device includesat least four measuring strips. When a plurality of measuring strips areused, they may be configured in any suitable manner around the tip ofthe integrated device (equally spaced around the circumference of theocular contact surface, symmetric or asymmetrically placed around thecircumference of the ocular contact surface, etc.). For example, asshown in FIG. 44D, the measuring strips may be configured to span thedesired 90 degree angle (45 degrees plus 45 degrees between the fartheststrips) to allow for a 90 degree rotation of a control lever withouthaving to reposition the hand of the user.

In some variations, the measuring component may be configured as amarking tip member (97). As shown in FIG. 12, the marking tip member(97) at its distal end (closer to the eye) that interfaces with theocular surface and leaves a visible mark (98) on the conjunctivalsurface when pressed against it (e.g., FIG. 13). The marker-tip enablesintraocular injections to be carried out through a safe area of the eyerelative to the corneo-scleral limbus (99), such as between about 3 mmand about 4 mm posterior to the limbus, over the pars plana region ofthe ciliary body of the eye. The diameter of the marking tip may rangefrom about 1 mm to about 8 mm, or from about 2 mm to about 5 mm, or fromabout 2.3 mm to about 2.4 mm (e.g., FIG. 12).

In further variations, the measuring component may be a sectoralmeasuring component. The sectoral measuring component may be configuredto span a sector of between about 1 degree and about 180 degrees of arc(e.g., between about 45 degrees and 90 degrees of arc) at the distal endof device or housing. In general, by “sectoral” it is meant that only aportion or section of the measuring component includes elements fortaking measurements. For example, a sectoral measuring component mayinclude radially extending members that are spaced from about 1 degreeto about 90 degrees about the circumference of the device tip. Duringprecise localization of the injection site, a sectoral measuringcomponent configured in this manner may enhance sterility of theprocedure because the measuring component can be oriented toward thelimbus and away from periocular appendages such as the eyelids and eyelashes. Here the sectoral measuring component may avoid contact with theappendages, thus minimizing the risk of bacterial contamination andintraocular infection, while enabling precise localization of theinjection site relative to the limbus in a sterile manner.

In one variation, the sectoral measuring component may comprise acentral (core) member having a proximal end and a distal end, andcomprising a plurality of radially oriented spokes or tabs as theradially extending members, which are equal in length. Central membermay be round, oval, square, rectangular or triangular in shape having acircumference or a perimeter. When central member is round, its diametermay be between about 1.0 mm and about 8.0 mm, or between about 3.0 mmand about 6.0 mm. Radially extending members may have the same fixedangle between any two adjacent members, for example, between 1 degreeand 90 degrees, or between 15 degrees and 45 degrees. The radiallyextending members may also have the same length, so that the distancebetween the needle exit point and the tip of each individual radialmember tip is substantially the same, for example between about 1.0 mmand about 5.0 mm, or between about 3.0 mm and about 4.0 mm. With thisconfiguration, the sectoral measuring component may provide fineadjustment of device positioning on the ocular surface around the limbuscircumference while rotating the entire device between 1 and 180 degrees(or between 1 and 90 degrees) and using any one or plurality of spokesor tabs to measure the distance between injection site and the limbus.As shown in FIG. 47, using any single tab or spoke (1002), or any twoadjacent tabs or spokes (1002) of a sectoral measuring component (1000)that simultaneously touch the limbus line enables the measurement of twofixed distances relative to the limbus, for example 4 mm and 3.5 mm,respectively. More specifically, when the measuring component is rotatedso that the tip of only one tab or spoke touches the limbus line whilethe tab or spoke is perpendicular to the limbus line, the injection siteis localized at about 4 mm (ranging from about 3 mm to about 5 mm) fromthe limbus. When the measuring component is rotated so that the tips oftwo tabs or spokes are simultaneously touching the limbus line, theinjection site is at about 3.5 mm from limbus (ranging from about 1 mmto about 4 mm).

In another variation, three divergent measuring tabs or spokes maycomprise the measuring component. In a further variation, two divergentmeasuring tabs or spokes may comprise the measuring component. Thedivergent measuring tabs or spokes may span a curvilinear distancebetween about 30 degrees and about 180 degrees or between about 45degrees and about 90 degrees on the distal surface of the device tip.Having the measuring tabs or spokes protrude only on one side of thedevice tip that is oriented towards the limbus and away from the eyelidmay be helpful in ensuring that the measuring tabs do not becomecontaminated by touching the eyelids or eyelashes.

In yet another variation, the measuring component, e.g., one having tabsor spokes as described above, may be configured to form a device tipthat couples to a slidable shield by an interference fit. For example,as shown in the cross-sectional view of FIG. 60, device tip (3000)includes a measuring component (3002), notch (3004), and a needlestabilization mechanism, tunnel (3006). The device tip (3000) may bemade from any suitable polymer, e.g., a polymer having a durometerbetween about 2 A and about 70 A, about 40 A and about 70 A, or betweenabout 5 A and about 60 A. Alternatively, the device tip may be made froma polymer such as silicone or a thermoplastic elastomer such asMedalist® TPE, e.g., TPE MD-105 (18 durometer Shore A) or TPE MD-100thermoplastic elastomer (5 durometer Shore A). A flange (3008) on thedistal end of the shield (3010) correspondingly fits into notch (3004)to form the interference fit. Such an interference fit is beneficialbecause it may better hold the device tip within the shield.

Conduits

The intraocular drug delivery devices described here may include anysuitable conduit (or dispensing member) for accessing the intraocularspace and delivering active agents therein. The conduits may have anysuitable configuration, but will generally have a proximal end, a distalend, and a lumen extending therethrough. In their first, non-deployed(pre-deployed) state, the conduits will generally reside within thehousing. In their second, deployed state, i.e., after activation of theactuation mechanism, the conduit, or a portion thereof, will typicallyextend from the housing. By “proximal end” it is meant the end closestto the user's hand, and opposite the end near the eye, when the devicesare positioned against the eye surface. In some variations, the drugconduit is removable or detachable from the drug reservoir. In othervariations, the drug conduit is permanently (fixedly attached) to thedrug reservoir.

The distal end of the conduit will generally be configured to be sharp,beveled, or otherwise capable of penetrating the eye surface, e.g., thesclera. The conduit employed may be of any suitable gauge, for example,about 25 gauge, about 26 gauge, about 27 gauge, about 28 gauge, about 29gauge, about 30 gauge, about 31 gauge, about 32 gauge, about 33 gauge,about 34 gauge, about 35 gauge, about 36 gauge, about 37 gauge, about 38gauge, or about 39 gauge. The wall of the conduit may also have anysuitable wall thickness. For example, in addition to regular wall (RW)thickness, the wall thickness of the conduit may be designated as thinwall (TW), extra/ultra thin wall (XTW/UTW), or extra-extra thin wall(XXTW). These designations are well known to those of skill in therelevant art. For example, the conduit may be a fine gauge cannula orneedle. In some variations, the conduits may have a gauge between about25 to about 39. In other variations, the conduits may have a gaugebetween about 27 to about 35. In yet further variations, the conduitsmay have a gauge between about 30 to about 33. Use of a small needlegauge, for example a 31-33 gauge needle, may make the needle trackthrough the sclera smaller and may minimize the risk of the drugbackflow from the eye along with the egress of intraocular fluidfollowing intraocular needle withdrawal.

In some variations, the outer diameter of the needle may be tapered froma wider needle base toward a narrower needle tip. In another example,the needle inner diameter may be tapered from a wider needle base towarda narrower needle tip. In yet another example, both the needle outer andinner diameters may be tapered from a wider needle base toward anarrower needle tip. For example, either or both needle diameters may betapered from about 25 to about 27 gauge at the base toward about 31 toabout 33 gauge at the tip, or from about 30 gauge at the base towardabout 32 to about 33 gauge at the tip.

The conduits may have a sharp, pointed tip (FIGS. 14B-14C and FIGS.15A1-15A2), rather than a rounded one (FIG. 14A) as in conventionalneedles. The pointed needle tip is formed by the lateral side surfacesthat are straight at the point of their convergence into the tip, and atthe point of their convergence forming a bevel angle (the angle formedby the bevel and the shaft of the needle), which may range from betweenabout 5 degrees and about 45 degrees (FIG. 14B), between about 5 degreesand about 30 degrees, between about 13 degrees to about 20 degrees, orbetween about 10 degrees and about 23 degrees (FIG. 14C).

The sharp, pointed needle tip may provide improved penetration of theneedle through the fibrillar, fibrous scleral tissue, which is the majorstructural cover of the eye and consists of a network of strong collagenfibers. Thus, such a needle tip during its penetration through the eyewall may create less resistance and, thus, decrease the impact forcethat is transmitted to the intraocular structures, such as the retinaand the crystalline lens, in turn causing less damage to intraocularstructures during the intraocular injection process (compared toconventional needles).

In addition, such a narrow bevel angle may enable the needle to causeless sensation when it penetrates through the eye wall (the outer coverof the said eye wall being richly innervated with sensory nerve fibersendings particularly densely located in the conjunctiva and cornea),which may be an issue when intraocular injections are involved comparedto other less sensitive sites.

The narrow bevel angle may also allow for a longer bevel length andlarger bevel opening and, thus, a larger opening at the distal end ofthe injection needle. With such a configuration, the force of druginjection into an eye cavity may be reduced, thus reducing the chancesof intraocular tissue damage by a forceful stream of injected substance,which may occur with conventional short-beveled needles.

In some variations, the conduits are injection needles having one ormore flat surface planes, as well as one or more side-cutting surfaces,as illustrated in FIGS. 16 and 17. Examples include a needle shaftcomprising multiple surface planes separated by sharp ridges (FIGS.16A-16C), as well as a needle tip comprising sharp side-cutting surfaceslocated on either side of the beveled surface of the needle about 90degrees from the beveled surface (FIG. 17). The conduit may also bebi-beveled, i.e., have two bevels facing about 180 degrees from eachother that is located on the opposite sides of the conduit. The conduitmay also be coated (e.g., with silicone, PTFE, etc.) to facilitate itspenetration through the eye wall.

In other variations, the conduit may be configured to be wholly orpartially flattened in at least one dimension, as shown in thecross-sectional view of FIG. 18C taken along the line A-A of FIG. 18A.For example, the conduit may be flattened in the anterior-posteriordimension (that is from the beveled side of the needle towards itsopposite side. In one variation, both the external and internal surfacesof the needle are flattened and represent ovals on cross-section. Inanother variation, the internal surface of the needle is round andrepresents a circle on cross-section, while the external surface of theneedle is flattened to enable its easier penetration through the fibrousscleral or corneal tissue of the eye wall. In another variation, morethan one external surface plane of the needle is flattened to enable itseasier penetration through the fibrous eye wall, while the internalopening of the said needle may be of any shape including round or oval.

As previously stated, in its second, deployed state, the conduit orneedle extends from the housing. The portion of the needle that extendsfrom the housing can be referred to as the exposed needle length. Uponactivation of the actuation mechanism, the needle goes from its first,non-deployed state (pre-deployed state) (where it is entirely within thehousing of the device), to its second, deployed configuration outsidethe housing, where a certain length of it is exposed. This exposedlength may range from about 1 mm to about 25 mm, from about 2 mm toabout 15 mm, or from about 3.5 mm to about 10 mm. The exposed needlelengths may enable complete penetration through the eye wall and intothe vitreous cavity, while minimizing the risk of intraocular damage.The exposed needle length may be adjusted according to the depth ofneedle penetration desired. In some variations, the exposed needlelength ranges from about 1 mm to about 25 mm, or from about 1.5 mm toabout 10 mm, or from about 2 mm to about 8 mm. Here the exposed needlelengths may enable complete intraocular penetration through the corneainto the anterior chamber, while minimizing the risk of intraoculardamage. To illustrate, if the injection depth is too shallow, the drugcould be injected into the choroid causing bleeding, or into thecortical gel causing a retina tear. If the injection is too deep, thejet stream or hydraulic wave generated by the injected drug could causetrauma to the lens or the retina/macula on the opposite side of the eye.An exemplary range of needle exposure past the external surface of thedevice tip is between about 4 to about 6 mm, or between about 2 to about8 mm, or between about 1 mm to about 25 mm. If the injection depth istoo shallow, the drug may leak out of the eye due to backflow of theintraocular fluid through the needle track. This may result in variableintraocular drug concentration following injections. To minimize this,it may be beneficial for the needle to (be exposed and) have apenetration depth of at least about 2 mm (or at least about 4 mm, or atleast about 6 mm), and have a small needle gauge that may produce aself-sealing wound (for example 30 gauge or smaller, or in the range of30-33 gauge).

In some variations, the devices may include an exposure controlmechanism (9) for the dispensing member (11) (conduit) (FIGS. 19 and20). The exposure control mechanism (9) generally enables one to set themaximal length of the dispensing member exposure during dispensingmember deployment. In one variation, the exposure control mechanismworks by providing a back-stop for the needle-protective member (13). Inanother variation, the exposure control mechanism (9) may be a rotatingring member with a dialable gauge. Needle exposure could be adjusted bythe millimeter or a fraction of the millimeter, e.g., 1 mm, 1.5 mm, 2mm, 2.5 mm, 3 mm, etc. Here the device may be equipped with a retractionmechanism that controls needle retraction into a needle-protectivemember. Such a needle-retraction mechanism may be spring-actuated (FIG.20).

The devices may also include a removable distal (towards the eye) memberthat covers and protects the conduit (e.g., the front cover (15) in FIG.21). In one variation, the devices may also include a removable proximal(away the eye) member that covers and protects the proximal part of thedevice, e.g., comprising a loading dock mechanism (17) (e.g., the backcover (19) in FIG. 21).

Some variations of the devices described herein comprise a needlestabilization mechanism or needle guide mechanism configured to providea steady and consistent needle alignment that is perpendicular to theocular contact surface, and, therefore, perpendicular to the eyesurface. This allows the operator to precisely control the angle ofneedle penetration into the eye by controlling the position of thedevice tip and housing relative to the eye surface. For example, theneedle stabilization mechanism may be configured so that the needleexits the device tip through its central point (e.g., at the geometriccenter of a round tip) at 90 degrees relative to the tip outer surface(e.g., the ocular contact surface). Referring to FIG. 56, the needlestabilization mechanism may be configured as a tunnel (1800) thatextends through the distal end of the device, e.g., through the ocularmeasuring component (1802) to open to the device exterior at the centerof the device tip. In another variation, as shown in FIGS. 57A and 57B,the needle stabilization mechanism is configured as a sheath or scabbard(1902). In some instances, an injection angle other than 90 degrees(when the long axis of the device is not completely perpendicular to theeye surface at the injection site), may lead to inadvertent intraoculartrauma to the crystalline lens or the retina. However, in otherinstances it may be useful for the needle to exit the tip at an angleless than 90 degrees relative to eye surface, in a direction parallel tothe limbus.

In addition to allowing the injection needle to remain centered withrespect to the injection device during the injection procedure, theneedle stabilization mechanism may also be configured to include ananti-bending component that prevents bending of the needle while it isbeing advanced into the eye. In some variations, the needlestabilization mechanism is made of a non-deformable material, such aspolycarbonate. In other variations, the needle stabilization mechanismis part of the slidable shield, or may be detachable or fixedlyconnected to the shield.

A drug conduit such as a needle used with the devices described hereinmay bend at its base (e.g., where it is inserted into the hub) or nearthe center of the needle shaft during advancement through the eye wall.The needle stabilization mechanism may be configured to support theneedle as it is being deployed. Thus, the needle stabilization mechanismmay have a certain length and/or inner diameter relative to the encloseddrug conduit. In general, the needle stabilization mechanism will have aminimal (and optionally uniform) length and/or maximum innercross-sectional diameter. The needle stabilization mechanism may also bedefined by a ratio of its length to its inner cross-sectional diameter(to distinguish an opening in a shield that would be relatively short).As previously mentioned, the needle stabilization mechanism may have acertain length and/or inner diameter (ID) relative to the dimensions ofthe enclosed drug conduit. For example, the needle stabilizationmechanism may have an axial length of between about 5% to about 95%,about 20% to about 60%, or about 20% to about 50% of the needle axiallength. In some variations, the needle stabilization mechanism has an IDranging from about 30% to 100%, from about 50% to about 95%, or fromabout 50% to about 90% of the outer diameter (OD) of the drug conduit.In one variation, the ID of the needle stabilization mechanism isgreater than the OD of the drug conduit. The needle stabilizationmechanism or guide mechanism may allow the utilization of smaller gaugeneedles or larger gauge but thinner walled needles (as compared toconventional needles), which may be particularly beneficial when largemolecular drugs that include peptides, proteins, antibodies, solublereceptors, etc., are delivered. In some variations, such a needlestabilization mechanism may be configured as a tunnel, sheath, orscabbard in which the needle is coaxially disposed. The needle may becompletely covered inside its needle stabilization mechanism during theresting position. During needle deployment, about 4 mm to about 10 mm ofthe needle tip may be exposed outside of the needle stabilizationmechanism. Furthermore, the needle stabilization mechanism may beconfigured so that the needle travels directly through it and into theeye without contacting air.

The central positioning and anti-bending features of the needlestabilization mechanism may be particularly beneficial in preventingbending of smaller gauge needles, for example 31 gauge to 35 gaugeneedles. The utilization of smaller gauge needles is particularlydesirable for intraocular injections because the opening such a needlemakes in the eye wall is smaller, thereby eliminating or reducing theback flush of intraocular fluid following needle withdrawal. Eliminatingor reducing the backflush of intraocular fluid has other advantages. Forexample, communication between the outside environment and the interiorof the eye is avoided or minimized (or the time period that thecommunication exists is eliminated or reduced), in turn reducing therisk of intraocular infection or endophthalmitis. Additionally, the useof a smaller needle gauge enhances patient comfort during intraocularneedle penetration, which is inversely proportional to the needle gauge.Furthermore, the anti-bending and central positioning features are alsobeneficial when thin walled needles are utilized for intraocular drugdelivery of high-viscosity, high molecular weight, or large particledrugs.

When a shielded drug conduit (e.g., an injection needle) is completelycovered inside its shield, a priming solution, gel, or suspension (e.g.,a drug) may drain back into the cavity of the shield unless the needletip is exposed outside of the shield, which is undesirable from both theneedle sterility and accidental needle stick safety standpoints. Inorder to enable the priming of the injection needle with a drug whilethe needle tip is completely covered and without the drug leaking insidethe needle shield or its cavity, a priming-enabling component (PEC) fora shielded needle may be included inside the needle shield. In somevariations, the PEC could be a variation of the needle guide-tunneldescribed herein.

In one example, the priming-enabling component (PEC) comprises a narrowtunnel along its entire length (see, e.g., element 7014 in FIG. 65). Inanother example, as shown in FIG. 66A, the priming-enabling componentcomprises a needle tunnel with a segment having a narrower internaldiameter (8000) and a segment having a wider internal diameter (8002)(e.g., a step-wise tunnel). Here the narrow segment is proximal to thewide segment. An injection needle (8006), slidable sleeve (8008), safetyclip (8010), and hub or female-type luer connector (8012) are alsoshown. In yet another example, as shown in FIG. 66B, the PEC comprises aneedle tunnel having multiple narrow segments (8000) and at least onewide segment (8002). In one variation, all multiple narrow segments or“steps” in the tunnel have the same length. In another variation, themultiple narrow segments or “steps” in the tunnel have differentlengths. In one variation, all multiple narrow segments or “steps” inthe tunnel have the same internal diameter. In another variation, themultiple narrow segments or “steps” in the tunnel have differentinternal diameters. In yet further variations, the diameter of theneedle tunnel may expand at its distal end to form a funnel or conicalshape (8004 in FIG. 66C).

Due to increased friction and resistance to the movement of the shield,such as when a slidable shield slides longitudinally along the injectionneedle, the limited length of the narrow segment or step of the needletunnel, while the rest of the tunnel is wider, ensure that there is noexcessive friction or resistance between the injection needle and theslidable shield movement.

Thus, the length of the narrow segment or step of the needle tunnel maybe directly proportional to the resistance force of the slidable shield,whereas the ratio of the diameter of the resistance-controllingcomponent of the tunnel versus the outer diameter of the injection drugconduit (e.g., injection needle) may be constant.

The diameter of the narrow (i.e., priming-enabling) portion or step inthe tunnel can range from being slightly larger than the needle's outerdiameter (OD) to slightly smaller, for example ±0.12 mm (0.005″) of theneedle OD.

Examples of the injection needle OD relation to the diameter of thepriming-enabling component (PEC) of the needle tunnel are as follow:

Injection needle outer diameter: PEC internal diameter: 0.20 mm 0.20 ±0.12 mm 0.22 mm 0.22 ± 0.12 mm 0.24 mm 0.24 ± 0.12 mm 0.26 mm 0.26 ±0.12 mm 0.28 mm 0.28 ± 0.12 mm 0.30 mm 0.30 ± 0.12 mm

In one example, the diameter of the narrow (i.e., priming-controlling)step in the guide tunnel is the same as the diameter of the needle OD.

Reservoirs

The reservoir is generally contained within the housing and may beconfigured in any suitable manner, so long as it is capable ofdelivering an active agent to the intraocular space using the actuationmechanisms described herein. The reservoir may hold any suitable drug orformulation, or combination of drugs or formulations to the intraocularspace, e.g., the intravitreal space. It should be understood that theterms “drug” and “agent” are used interchangeably herein throughout. Inone variation, the drug reservoir is silicone oil-free (lacks siliconeoil or one of its derivatives) and is not internally covered orlubricated with silicone oil, its derivative or a modification thereof,which ensures that silicone oil does not get inside the eye causingfloaters or intraocular pressure elevation. In another variation, thedrug reservoir is free of any lubricant or sealant and is not internallycovered or lubricated with any lubricating or sealing substance, whichensures that the said lubricating or sealing substance does not getinside the eye causing floaters or intraocular pressure elevation.

In some variations, the reservoir is made of a material that contains acyclic olefin series resin, a cyclic olefin ethylene copolymer includingcommercially available products such as Zeonex® cyclo olefin polymer(ZEON Corporation, Tokyo, Japan) or Crystal Zenith® olefinic polymer(Dalkyo Seiko, Ltd., Tokyo, Japan) and APEL™ cyclo olefin copolymer(COC) (Mitsui Chemicals, Inc., Tokyo, Japan), a cyclic olefin ethylenecopolymer, a polyethylene terephthalate series resin, a polystyreneresin, a polybutylene terephthalate resin, and combinations thereof. Inone variation, it may be beneficial to use a cyclic olefin series resinand a cyclic olefin ethylene copolymer that have a high transparency, ahigh heat resistance, and minimal to no chemical interaction with apharmacological product such as a protein, a protein fragment, apolypeptide, or a chimeric molecule including an antibody, a receptor ora binding protein.

Exemplary agents may be selected from classes such asanti-inflammatories (e.g., steroidal and non-steroidal), anti-infectives(e.g., antibiotics, antifungals, antiparasitics, antivirals, andantiseptics), cholinergic antagonists and agonists, adrenergicantagonists and agonists, anti-glaucoma agents, neuroprotection agents,agents for cataract prevention or treatment, anti-oxidants,antihistamines, anti-platelet agents, anticoagulants, antithrombics,anti-scarring agents, anti-proliferatives, anti-tumor agents, complementinhibitors, vitamins (e.g., vitamin B and derivatives thereof, vitaminA, depaxapenthenol, and retinoic acid), growth factors, agents toinhibit growth factors, gene therapy vectors, chemotherapy agents,protein kinase inhibitors, tyrosine kinase inhibitors, PEGF (pigmentepithelial growth factor), small interfering RNAs, their analogs,derivatives, conjugates, and modifications thereof, and combinationsthereof.

Exemplary complement inhibitors include, but are not limited to,antibodies or blocking peptides that inhibit at least one complementprotein or fraction (e.g., anti-C5 agents, including antibodies such asanti-C5a and anti-C5b agents, and ARC1905; anti-C3 agents andantibodies, such as anti-C3 and anti-C3b, and other complementinhibitors, complement fraction inhibitors, or combinations thereof.

Particular agent classes that may be useful include without limitation,anti-neovascularization agents, anti-VEGF agents, anti-platelet derivedgrowth factor agents, anti-placenta derived growth factor agents,anti-pigment epithelium derived growth factor agents, anti-PDGF pathwayblocking agents (e.g., a PDGF-beta pathway blocking agent such asanti-PDGF-beta aptamers (e.g., Fovista™ anti-PDGF therapy), antibodies,blocking peptides or blocking small molecules), anti-PDGF-beta receptoragents (e.g., a PDGFR-beta blocking agent such as an aptamer, antibody,blocking peptide, or a blocking small molecule), anti-vascularpermeability agents, protein kinase C inhibitors, EGF inhibitors,tyrosine kinase inhibitors, steroidal anti-inflammatories, nonsteroidalanti-inflammatories, anti-infectives, anti-allergens, cholinergicantagonists and agonists, adrenergic antagonists and agonists,anti-glaucoma agents, neuroprotection agents, agents for cataractprevention or treatment, anti-proliferatives, anti-tumor agents,complement inhibitors, vitamins, growth factors, agents to inhibitgrowth factors, gene therapy vectors, chemotherapy agents, proteinkinase inhibitors, small interfering RNAs, aptamers, antibodies orantibody fragments, growth factor receptors and receptor fragments,analogs, derivatives, and modifications thereof, and combinationsthereof. Further exemplary agents include an anti-complement fractionagent (e.g., an anti-C5 agent, anti-C5a agent, or anti-C3 agent) andaptamers, antibodies, and binding peptides thereof, and combinationsthereof. In one variation, a combination of an anti-VEGF agent and ananti-PDGF agent is used.

Non-limiting, specific examples of drugs that may be used alone or aspart of a combination drug therapy include Lucentis™ (ranibizumab),Avastin™ (bevacizumab), Fovista™ (anti-PDGF therapy), E10030 aptamer,Macugen™ (pegaptanib), anti-complement agents as described above,steroids, e.g., dexamethasone, dexamethasone sodium phosphate,triamcinolone, triamcinolone acetonide, and fluocinolone, taxol-likedrugs, integrin or anti-integrin agents, vascular endothelial growthfactor (VEGF) trap (aflibercept) (VEGF receptor fragments or analogs),anecortave acetate (Retaane), enzymes, proteases, hyaluronidase,plasmin, ocriplasmin, and limus family compounds, and combinationsthereof. Non-limiting examples of members of the limus family ofcompounds include sirolimus (rapamycin) and its water soluble analogSDZ-RAD, tacrolimus, everolimus, pimecrolimus, and zotarolimus, as wellas analogs, derivatives, conjugates, salts, and modifications thereof,and combinations thereof. In some instances it may be beneficial toemploy a combination of agents. For example, it may be beneficial tocombine two or more of the following for therapy: Lucentis™(ranibizumab), Fovista™ (anti-PDGF therapy), Eylea® (aflibercept), ananti-PDGF agent, Macugen™, Jetrea™, a thrombolytic agent, and a steroid.In some instances it may be beneficial to combine Lucentis™(ranibizumab) and Fovista™ (or another anti-PDGF agent) combination, orEylea® (aflibercept) and Fovista™ (or another anti-PDGF agent).

Topical anesthetic agents may also be included in the reservoirs. Forexample, lidocaine, proparacaine, prilocalne, tetracaine, betacaine,benzocaine, ELA-Max®, EMLA® (eutectic mixture of local anesthetics), andcombinations thereof may be used.

Some variations of the injection devices described herein include afilter that filters the contents of the reservoir as it is deliveredinto the eye. For example, the filter may be used to remove infectiousagents and enhance sterility of an active agent formulation beforeinjection into the eye. Thus, inclusion of a filter into the device maybe useful because the eye is an immune-privileged site, and introductionof even a small quantity of pathogens such as bacteria may causesight-threatening intraocular infection (endophthalmitis). The filtermay also be used to remove impurities, e.g., silicone droplets, from anactive agent formulation prior to injection into the eye. This may beuseful for intraocular drugs because a small impurity injected into asubject's eye may result in the subject seeing it as floater(s) that maybe intractable, which significantly worsens the quality of vision.

In one variation, the filter pore size is between about 0.1 μm (microns)and about 10 μm (microns), between about 0.2 μm (microns) to about 5.0μm (microns), or between about 0.2 μm (microns) and about 1.0 μm(microns) to facilitate filtration of bacterial pathogens, particulatematter or impurities such as silicone droplets from the outgoing drugbeing injected intraocularly. Thickness of the said may range frombetween about 50 μm (microns) to about 250 μm (microns), or from betweenabout 10 μm (microns) to about 10000 μm (microns).

The filter may be made from any suitable non-reactive material, such asa low protein-binding material. Exemplary filter materials includewithout limitation, thermoplastic fluoropolymers such as PVDF(polyvinylidene fluoride); thermoplastic polymers such as polyethyleneand polypropylene; mixed cellulose esters; nylons; polyesters;nitrocelluloses; acrylic polymers such as Versapor® acrylic copolymer;polyethersulfones such as found in Supor™ and Supor-R™ (Pall, Inc.)filters; a combination, a mixture, or a blend thereof.

The filter may be integrated with the device housing, the reservoir, theconduit, or any part of the device. In one variation, the filter ispress-fit into a device lumen, for example into the lumen of a male-typeluer, or a female-type hub, such as a drug conduit hub. In onevariation, the filter is internal to the device. For example, the filteris configured to be inside the drug reservoir, or inside the conduit, orat the junction between reservoir and conduit. In another variation,filter is detachable or removable from the device. In one variation, thefilter is located within the reservoir at its distal end, e.g., withinthe luer of a syringe. In another variation, the filter is located atthe proximal end of the lumen of the conduit. The filter may also beplaced at any location within and along the lumen of the drug deliveryconduit, e.g., at its proximal end, in the middle, or at the distal endof the conduit.

In one example, the filter is integrated with the drug-loading conduitor device utilized to load a drug into the intraocular drug deliverydevices described herein. For example, the filter is located inside thedrug-loading conduit, or at or near the internal opening of the lumen ofthe drug-loading conduit. The filter may also be placed at any locationwithin and along the lumen of the drug-loading conduit, e.g., at itsproximal end, in the middle, or at the distal end of the conduit. Forexample, integrating a sterilizing filter within the drug-loadingconduit may prevent microbial pathogens from room air from beingintroduced into the drug during the loading procedure.

In addition to removing infectious agents and/or impurities from thereservoir contents, the filter may function as a jet control mechanismthat controls the force and limits the travel distance of the injectedfluid as it exits the device and enters the eye. Other configurations ofthe jet control mechanism are also contemplated. The jet controlmechanism may be generally configured to limit the maximum traveldistance of the injected fluid to between about 5 mm and about 25 mm,between about 5 mm to about 20 mm, between about 5 mm and about 15 mm,or between about 5 mm to about 10 mm. In some instances, the maximumtravel distance may be limited to less than about 25 mm, less than about15 mm, less than about 10 mm, or less than about 5 mm. When a filterserves as the jet control mechanism, the pore size may range from about0.05 μm to about 10 μm, from about 0.1 μm to about 5 μm, or from about0.2 μm to about 1 μm. Such a filter may also be placed within anyportion of the device, e.g., near the device conduit.

The jet control mechanism may also include a fluid displacement controlmechanism. The fluid displacement control mechanism may include aplunger rate control mechanism such as a mechanical interference,resistance component, or pneumatic control component that is configuredto control the rate of plunger advancement within the reservoir of thedevice. The jet control mechanism may be beneficial because it improvesthe safety of intraocular drug injections, e.g., by minimizing the riskof serious adverse effects such as retinal detachment or other types ofdamage to intraocular structures by a forceful jet of fluid inside theeye.

It may also be advantageous to remove air from the reservoir contentsbefore it is injected into the eye since the presence of intraocular aircan result in unpleasant visual disturbances (“floaters”). The removalof air from a viscous composition, e.g., a viscous drug solution such asLucentis® (ranibizumab injection), may be particularly beneficial. Thus,in some variations, the devices described herein may also include an aircontrol mechanism for removing the amount of air introduced into the eyeduring intraocular drug administration. The air removal mechanism may beconfigured as a filter, a plurality of filters, a valve, a reservoir, ora combination of any of the foregoing. The air removal mechanism may beplaced within any portion of the device, e.g., near the device conduit.

Some variations of the air control mechanism may include a hydrophobicfilter or porous hydrophobic membrane that allows air through whileretaining an aqueous drug solution. Exemplary materials that may beemployed in the hydrophobic filters include without limitation,polytetrafluoroethylene (PTFE), Supor® R Membrane (Pall Corporation, AnnArbor, Mich.), Versapor® R Membrane (Pall Corporation, Ann Arbor,Mich.), and other porous filter materials that have been coated ortreated with a hydrophobic membrane such as Repel™ Acrylic CopolymerMembrane (Pall Corporation, Ann Arbor, Mich.). The pore size of the airremoval filters may range from about 0.05 μm to about 50 μm, from about0.1 μm to about 10 μm, or from about 0.2 μm to about 5 μm.

Some variations of the air control mechanism may include a (e.g.,proximal) extension of the drug conduit and its internal opening (or itsholder or internal opening of the hub of the drug conduit) into theinternal cavity of a syringe luer or drug reservoir (e.g., beyond theinternal surface plane of the hub). Such proximal extension of the drugconduit and its internal opening beyond the internal surface of its hubmay provide an internal hub-luer seal (e.g., between the female-typehub, such as a disposable needle hub, and male-type luer, such as asyringe luer), where the seal prevents air and/or fluid in the drugsolution or suspension from entering the cavity of the needle hub, butrather enables the air and/or fluid to pass directly from a drugreservoir into the drug conduit. For example, the said internal hub-luerseal may be generated by fit interference between the external surfaceof the proximal extension of the drug conduit or its internal hubcontinuation and the internal surface of the male-type luer of a drugreservoir, such as a syringe luer.

The internal hub-luer seal may be the only seal or a secondary sealbetween the drug conduit's hub and drug reservoir's luer, for example inaddition to the conventional seal between the external surface of thesyringe luer and the internal surface of the needle hub cavity.

In one example, the proximal, internal extension of the drug conduit mayhave a conical or pyramidal shape with slanted or sloped external wallsin order to enable the creation of a tight seal as it enters the distalopening of a syringe luer or a drug reservoir. It may also enable thecreation of an air- and/or water-tight seal between the drug conduit anda variety of different syringe luers having different internal diameter.In one variation, the external diameter of the distal end of the conduitproximal extension is different than that of its proximal end. Forexample, the distal end diameter is larger than the proximal endexternal diameter of the conduit's extension. For example, the angle ofthe sloped external walls of the proximal drug conduit extension may bebetween 1 degree and 45 degrees, or between 3 degrees and 30 degrees, orbetween 5 degrees and 15 degrees.

Given that the internal diameter angle of the standard syringe luer is1.8 degrees, a larger angle of the sloped conduit extension walls may beneeded to enable an internal luer seal. While the injection device isbeing attached to a drug reservoir (i.e., a luer syringe), the sequenceof steps may be such that the syringe luer is locked with the injectiondevice hub followed by the creation of an internal luer seal. Thus, acertain angle of the sloped walls of the conduit extension may berequired for the internal seal to form. Creation of an internal luerseal may also depend on the inside diameter of the syringe luer and thelength of the luer-lock component.

The internal hub-luer seal may prevent air bubbles from entering thedrug conduit and being injected into the eye causing bothersome“floaters”. For example, air bubbles passing by the drug conduit'sinternal opening during its priming may pass into the proximal part ofthe hub and get trapped there, or continue to pass for example through afilter (e.g., a hydrophobic filter) out of the hub. In addition,proximally extended drug conduit's internal opening beyond the internalplane of its hub may prevent potential clogging of the drug conduit bythe glue used to attach the needle to the hub. This way, the needleshaft rather than its proximal open end will be glued into the hub,reducing the chance of glue clogging the needle or interacting with thedrug.

In one variation, the drug conduit may comprise more than one internaland/or external diameter. For example, the proximal part of the drugconduit, some or all of which may penetrate the eye wall, may have asmall internal and/or external diameter (e.g., 33 gauge, or within the30 to 33 gauge range) whereas its proximal portion may have a largerinternal and/or external diameter (e.g., 30 gauge, or within the 25 to31 gauge range). In one example, the proximal portion of the drugconduit comprises a narrower, 31 gauge or 32 gauge or 33 gauge needle,whereas the proximal portion of the drug conduit comprises a wider, 25to 30 gauge needle.

In some variations, the drug conduit comprises a needle with at least aportion being tapered (e.g., internal, external, or bothinternal/external diameter being narrower towards its distal end). Inone variation, the drug conduit comprises a needle with at least twoportions, or the entire needle being tapered (e.g., narrower internal,external or both internal/external diameter towards its distal end).This design allows for the proximal portion of the drug conduit (thatdoes not penetrate the eye wall or enter an eye cavity) to have widerdiameter therefore reducing the overall resistance to the drug flowwhile maintaining patient comfort due to the small needle gauge comingin contact with the eye. Such drug conduit having reduced resistance todrug flow is particularly important when using large molecular sizedrugs (such as proteins and other biopharmaceuticals), small-gaugeneedles (such as 30 to 33 gauge needles), or using proximally extendedand elongated needles described herein.

In one variation, the proximal extension of the drug conduit or a tunnelconnected to the drug conduit into the female-type luer connector or hubof the device (e.g. internal luer connector), may be able to puncture amembrane, a stopper, or a cap covering the distal entrance into the drugreservoir cavity, for example a syringe luer. This may be used withloadable and prefilled drug reservoirs or syringes, and may ensure theair-free drug injection. Such internal luer connector may also minimizethe dead volume of a device-drug reservoir system, and enhancesterility. In one example, the internal luer connector (e.g., as shownin FIG. 65 as element 7012) has a conical shape with sloped externalsurface and comprises a proximal extension of the drug conduit (e.g., asshown in FIG. 65 as element 7016) extending distally beyond the proximaledge of the conical luer extension and into the cavity of a drugreservoir such as a syringe luer.

In some variations, there is a two-step connection between the deviceand a drug reservoir. In one example, the drug injector comprising suchan internal luer connector may be removably attached to a drug-prefilledsyringe or container, but with a membrane seal intact preventing drugexposure to air (e.g. enabling a first-step connection). When the deviceis ready to be used, the internal luer connector is advanced furtherproximally without removing the device to enable its penetration throughthe membrane seal and provide direct communication between the internalopening of the drug conduit and the drug (e.g. enabling a second-stepconnection). Such proximal advancement of the internal luer connectorthrough the membrane or seal covering a drug reservoir distal entrancemay be achieved by turning the luer lock mechanism or a similar luerconnection mechanism, for example, a quarter or half turn. In anotherexample, the proximal advancement of the internal luer connector tobreak the drug seal may be achieved by snapping the device hub furtheronto the external luer connector.

The devices described herein may further include a terminalsterilization mechanism that includes a filter for removing infectiousagents and particulate matter (as previously described) alone, or incombination with an air removal mechanism, e.g., an air removal filter.The terminal sterilization mechanism generally removes bacteria andparticles from the drug solution as it exits the device and enters theeye. The inclusion of a terminal sterilization mechanism may help tominimize the risk of intraocular infection or inflammation such asendophthalmitis or sterile uveitis. The terminal sterilization mechanismmay be configured as a filter comprising a hydrophilic membrane that isplaced within any portion of the device, e.g., near the device conduit.The pore size of such a filter may range from about 0.05 μm to about 10μm, from about 0.1 μm to about 5 μm, or from about 0.2 μm to about 1 μm.In some variations, the filter is a non-protein binding or lowprotein-binding filter. Here exemplary hydrophilic filter materialsinclude without limitation, thermoplastic fluoropolymers such aspolyvinylidene fluoride (PVDF), mixed cellulose esters, nylons,polyesters, nitrocelluloses, and combinations, mixtures, or blendsthereof. In one variation, the hydrophilic filter is treated with anoleophobic material to repel oil. The oleophobic material may besilicone oil.

It is understood that the injection devices described herein may includean air removal mechanism, a terminal sterilization mechanism, a jetcontrol mechanism, or any combination thereof. When a plurality offilters are employed (e.g., in a filter assembly), both hydrophobic andhydrophilic filters may be used. In some instances, non-protein bindingor low protein-binding filters are used. For example, as shown in FIG.53, a filter (1510) may be provided near the device conduit (needle,1514) that removes bacteria and particles, and which also controls thetravel distance of the injected fluid. Thus, filter (1510) functions asboth a terminal sterilization mechanism and a jet control mechanism.Additionally, an air removal mechanism (1512) may be included near thedevice conduit (needle, 1514). The air removal mechanism (1512) maycomprise one or more openings in hub (1502) that communicates with thearea external to the device, or a pouch or chamber that collects air.The openings and pouch/chamber may or may not include a filter or avalve.

An air removal mechanism may be particularly beneficial when an airbubble in a drug solution or suspension covers a substantial amount ofthe surface area of a poorly gas-permeable membrane such as ahydrophilic membrane. The air bubble generally increases resistance toflow of the drug composition, in turn decreasing its flow rate, tothereby cause an airlock. In other instances, e.g., when a fine porehydrophilic membrane with a small surface area is utilized (that ispoorly permeable to air), small air bubbles can aggregate on its surfaceand fuse into larger air bubbles that may eventually cause an airlock.Here the hydrophilic filter membrane may have a surface area less thanabout 25 mm², or less than about 9 mm², or less than about 4 mm². Inanother example, the effective filtration surface area of a hydrophilicmembrane may be between about 0.1 mm² and 100 mm², or between about 1mm² and 25 mm².

As a solution to the problem described above, a drug delivery device(e.g., an injector device) may be provided that comprises agas-resistance component (e.g., a hydrophilic filter) and a vent (e.g.,a hydrophobic filter). A hydrophilic filter membrane may increase theresistance to air or gas flow and prevent it from passing through a drugconduit while also diverting it through a hydrophobic filter vent andout of the device to facilitate air or gas removal from the drugcomposition. The vent and gas-resistance resistance components may beadjacent to each other. The vent and gas-resistance components may alsobe integrally formed with the needle hub or provided as separate,attachable/detachable components. The gas-resistance component may be atleast partially air-impermeable under any condition, or at leastpartially air-impermeable under certain conditions, e.g., when wetted.The gas-resistance component may prevent air in the drug compositionfrom entering a drug conduit. The vent may provide an anti-airlockmechanism, or a gas (air)-removal mechanism. For example, the vent maycomprise an air-release valve or a hydrophobic membrane.

In some variations, the gas-resistance component may comprise asterilization filter. For example, the gas-resistance component mayinclude a hydrophilic membrane, such as a hydrophilic membrane filterthat produces filter-sterilization of the drug composition as it passesthrough it and is ejected from the device. The hydrophilic filtermembrane may be flat, convex, or concave in order to facilitateaggregation and fusion of small air bubbles into larger ones, to helpwith their removal by the air-removal component. In other variations,the pore size of the hydrophilic membrane may be small, making it lesspermeable to air and causing small air bubbles to aggregate on itssurface and fuse into larger bubbles. The larger bubbles may enhancetheir removal by the air-removal component. The gas-resistance componentmay comprise a hydrophilic membrane with a pore size ranging betweenabout 0.02 μm and about 5 μm, or about 0.1 μm and about 1 μm. Somevariations of the hydrophilic membrane may have a pore size of about 0.2μm.

In yet further variations, the drug delivery device may include anoil-removal component. In one example, the oil-removal component is partof, e.g., removable attached to, or integrated with, a terminalsterilization component. The oil-removal component may be a combinationof a hydrophilic/oleophobic filter and at least onehydrophobic/oleophilic filter adjacent to or in close proximity to thehydrophilic filter. Oleophobic and oleophilic coatings may also be usedto impart oleophobic or oleophilic properties to the filters.

Other filter structures and filter assembly configurations are alsocontemplated. For example, in some instances the filter may bestructured to include a hydrophilic center and a hydrophobic periphery,or vice versa. These filters may have any suitable shape and geometry,e.g., the filters may be shaped to be flat, concave, convex, or discoid.In some variations, the filter assembly comprises filters of differenttypes, e.g., a first filter and a second filter, where one ishydrophilic and the other is hydrophobic. When dual filters areemployed, the filters may be arranged so that they are adjacent oneanother. The filters may be positioned so that a certain angle is formedbetween their surfaces, e.g., an angle between about 45 degrees andabout 135 degrees, or between about 70 degrees and about 110 degrees. Insome variations, the angle between the hydrophilic and hydrophobicfilters may be about 90 degrees. For example, a 90 degree angle may beformed by placing a hydrophilic filter in the needle hub near theproximal end of the needle lumen, and a hydrophobic filter(s) in thewall of the needle hub. The filter assembly may include more than twofilters and/or more than two types of filters in certain instances.

Referring to FIGS. 55A-55G, exemplary filter arrangements are shown. Thefilters may be placed in the needle hub or syringe luer, or if anintegrated injection device is being employed, in the device wall nearthe proximal end of the needle or in the drug reservoir. In FIG. 55A,needle hub (1700) is shown having a proximal end (1702), a distal end(1704), a needle (1706) extending distally from the distal end (1704),and a wall (1705). Here the dual filter assembly includes a hydrophilicfilter (1708) within the space (1710) defined by the needle hub wall(1705) positioned perpendicular (90°) to the axis of the needle (1706).Hydrophobic filters (1712) are disposed within the wall (1705). In FIG.55B, the needle hub (1700) from FIG. 55A is shown, but hydrophilicfilter (1708) follows the contour of the wall (1705) at the needle hubdistal end (1704) to take a concave shape (with respect to the needle).In FIG. 55G, hydrophilic filter (1708) takes a convex shape (withrespect to the needle).

Alternatively, as shown in FIGS. 55C and 55D, hydrophobic filters (1708)can be disposed within the wall (1705) and hydrophilic filter (1708) canbe provided in the needle hub within the space (1710) defined by theneedle hub wall (1705) near the proximal end of the needle. Hydrophobicfilter (1712) may be shaped to be convex (with respect to the needle),as shown in FIG. 55D.

In an integrated device, as shown in FIGS. 55E and 55F, the space (1710)would be defined by the wall (1714) of the device instead of the wall ofthe needle hub, and some of the filters would be disposed within thewall (1714) of the device instead of the wall of the needle hub. Thehydrophilic filter (1708) may be provided at the distal end (1716) ofthe device (FIG. 55E), or spaced proximally to the distal end (1716) ata certain distance (FIG. 55F). In both instances, the hydrophobicfilters (1712) may be disposed within the device wall (1714).

The reservoirs and devices described here may be suitable forintraocular administration of a very small volume of a solution,suspension, gel or semi-solid substance. For example, a volume betweenabout 1 μl and about 200 μl, or between about 10 μl and about 150 μl, orbetween about 20 μl and about 100 μl may be delivered. To that end, thedevice will generally have a very small “dead space,” which enablesintraocular administration of very small volumes.

The volume of a solution, suspension, gel or semi-solid substance may beeven smaller when injected into the eyes of children, infants, orpremature infants, where the intravitreal volume may be as small asabout 4.0 ml. Thus, an injection device as described herein that isconfigured to inject such a small volume may be beneficial to use whentreating retinopathy of prematurity or other diseases of the eye thataffect these populations. Such a device may deliver a micro-volume ofdrug, e.g., a volume less than about 50 μl. In some variations, themicro-volume injector may deliver between about 5.0 μl to about 30 μl ofdrug. In other variations, the micro-volume injector may deliver betweenabout 10 μl and about 25 μl of drug.

The housing of the micro-volume injector may have an outside diameter(OD) that is substantially the same, or the same, as that of a largervolume device. For example, the OD may range from about 3.0 mm to about11 mm, from about 5.0 mm to about 10 mm, or from about 6.0 mm to about9.5 mm. However, the drug reservoir within the housing will generallydefine an inner diameter (ID) that may be smaller. For example, the IDmay range from about 1.0 mm to about 5.0 mm, from about 1.5 mm to 5.0mm, or from about 2.0 mm and 3.0 mm, in order to precisely measure the asmall amount of a drug solution.

In some instances, the smaller ID may be achieved by thickening the wallof the drug reservoir to measure, e.g., between about 1.0 mm and 3.0 mm,or between about 1.2 mm and about 2 mm. In another example, this couldbe achieved by expanding the OD within the grip/handle area only, forexample, by adding an external handle, grip, or expander to increase theouter diameter (OD) of an area to range between about 3.0 mm and about11.0 mm, or between about 5.0 mm and about 10 mm, or between about 6.0mm and about 9.5 mm, while keeping the ID of the drug reservoir the samesmall size, for example, between about 1.0 mm and about 5.0 mm, orbetween about 1.5 mm and 5.0 mm, or between about 2.0 mm and 3.0 mm,throughout the entire or partial axial length of the drug reservoir.Thus, the wall thickness of the drug compartment may be thin (e.g.,between about 0.7 mm and about 1.2 mm, or between about 0.8 mm and about1.2 mm) in front of the handle/grip area in order to directly visualizethe drug within the drug reservoir during drug loading, as well as toensure complete air removal and to facilitate the priming of the deviceand drug conduit (e.g. needle).

In some variations, the internal radius of the reservoir of theinjection device is configured to be proportional to the drug injectionvolume. Here the plunger travel distance (L) within drug reservoir isconstant may equal 12.7 mm (+/−5 mm). Thus, for an incompressible fluid(e.g., a drug solution or suspension), the square of the internal drugreservoir radius is proportional to the drug injection volume. That is:Injection volume=πr2L andL=Injection volume/πr2L;where L is the plunger travel distance and r is the internal radius ofthe drug reservoir.

Using these formulas, the plunger travel distance and internal radius ofthe reservoir can be tailored to optimize delivery of small injectionvolumes. For example:

-   -   For an injection volume of 0.05 ml and a length (L) of 12.7 mm,        the radius will be 1.12 mm;    -   For an injection volume of 0.05 ml and a length (L) of 7.7 mm,        the radius will be 1.44 mm;    -   For an injection volume of 0.05 ml (L) and a length of 17.7 mm,        the radius will be 0.95 mm;    -   For an injection volume of 0.03 ml and a length (L) of 12.7 mm,        the radius will be 0.87 mm;    -   For an injection volume of 0.03 ml and a length of 7.7 mm, the        radius will be 1.11 mm; and    -   For an injection volume of 0.03 ml and a length of 17.7 mm, the        radius will be 0.74.

In one variation, and as shown in FIG. 62A, the intraocular injectiondevice (5000) for delivering a pharmaceutical formulation into the eyeincludes a housing (5002) (e.g., a syringe barrel), a small volumereservoir disposed within the housing and configured as described above(dimensions are defined by the radius and plunger travel distance) todeliver about 0.03 to about 0.05 ml of the formulation, and a plungeractuation lever (5004) that extends through a slot (5006) in the side(lateral) wall of the housing, and which is fixedly attached to aportion of the plunger (5008). The plunger actuation lever (5004) may bemanipulated by a fingertip, and may help to deliver small volumes and/orlow viscosity formulations requiring less force but higher jet streamcontrol. A back plunger (5010) may also be included (e.g., by attachmentto plunger (5008)) for devices that deliver viscous fluids. Thus, theplunger here may be considered a rear-side plunger. The use of a backplunger may help with the injection of larger volumes and/or viscousfluids that require increased force application to advance the plungerthat is substantially disposed within the housing. A resistancecomponent is not included in this particular design of the injectiondevice. The housing (5002) can be used with commercially availabledetachable needles or with the injector attachments described herein byattachment to luer (5014).

An expanded, cross-sectional view of the housing tip (5012) is shown inFIG. 62B. Here the housing tip (5012) includes a hydrophilic filter(5016) at the distal end of the plunger travel path. In the figure, thefilter (5016) is depicted as being distal to the plunger seal (5018) butproximal to luer fitting (5014). Some variations of the device may beconfigured the same as that shown in FIG. 62A, but without thehydrophilic filter.

The device reservoirs may be pre-loaded during the manufacturing processor loaded manually before the intraocular injection, as furtherdescribed below.

Drug Loaders

Front loading of an injection device when the drug is loaded through theinjection needle generally dulls the needle tip and removes at leastsome of the lubricant coating from the needle making it more difficultand uncomfortable for the needle to penetrate the target tissue. Thereis also a higher risk of contaminating the injection needle whilemanipulating it with a drug container. Back loading, for example throughthe plunger, often leads to wasting a significant amount of the drug,for example, more than 0.05-0.1 mL, which is undesirable with expensiveagents, as well as when smaller drug volumes are used, as is typicallythe case for intravitreal injections. Here total volumes in the range of0.05-0.1 ml are generally used. When a detachable needle is used, drugmay be lost in the syringe luer and needle hub when the loading needleis exchanged with an injection needle, and contamination of the steriledrug conduit may occur. Thus, it would be beneficial to have a front orside-loading mechanism that allows for direct loading of the drug intodrug reservoir without passing the drug through the tip of the drugconduit, exchanging or detaching the drug conduit, or losing asignificant volume of the drug during the loading process.

In view of the above, when a drug or formulation is to be loaded intothe reservoir of the devices described herein prior to intraocularinjection, a loading member may be employed. The loading member may beremovably attached to the distal end of the housing. For example, theloading member may function as a loading dock that quantitativelycontrols the volume of a liquid, semi-liquid, gelatinous, or suspensiondrug that is to be loaded into the device. For example, the loadingmember may comprise a dial mechanism (21) that allows the operator topreset a particular volume of a drug to be loaded into the device (FIGS.21 and 22). The loading may occur with a precision raging from about0.01 μl and about 100 μl, or from about 0.1 μl and 10 μl. Such a loadingmember may allow for loading the device reservoir with a liquid,semi-liquid, gelatinous or suspended drug in a particular volume equalor less than that of the drug storage container, which allows forairless loading of the drug into the device. This may be beneficialbecause air injected into the eye will result in the sensation of seeing“floaters” by the patient, which may be uncomfortable and distracting tothe patient particularly during driving or other similar activities.

As shown in FIG. 22, the drug loading mechanism (23) includes a widebase member (25) for upright loading of the reservoir (27) through itsproximal (further from the eye) end (29). Also shown are exemplary front(31) and back (33) covers, as well as a dialable control mechanism (21)for setting the loading and/or injection volume(s). In other variations,the devices comprise a loading mechanism such as a loading dock (35A),wherein the dock (35A) interfaces with a drug storage container (FIGS.25A-25B) such as a vial known to those skilled in the art and penetratesthrough the vial stopper to gain access to the drug contained inside thevial so that the drug could be loaded into the device reservoir. InFIGS. 25A-25B, the dock mechanism is located in the dependant positionso that the drug vial (37) is positioned directly above the dock so thatthe drug moves from the vial downward in the direction of gravity.

In one variation, the dock mechanism comprises a needle or a sharpcannula that has openings or fenestrations (39) at its base. The saidopenings or fenestrations are positioned immediately adjacent to theinternal aspect of the vial stopper when the loading dock penetratesinto the drug vial while in the desired loading position, which in turnenables airless drug loading into the device as well as complete drugremoval from the storage container. Airless drug loading may bebeneficial because it may prevent the patient from seeing smallintraocular air bubbles or “floaters.” Complete drug removal is alsobeneficial given that small drug volumes and expensive medications aretypically used.

Some variations of the loading mechanism comprise a cannula or needle.The length of such a needle or cannula is sufficient to penetrate intothe lumen of the drug reservoir. In one example, the length of theloading needle or cannula is such that its tip reaches the opposite wallof the drug lumen when it is inserted perpendicularly to the devicewall, in order to minimize the amount of air bubbles formed during drugloading. For example, the length of the loading needle or cannula isbetween about 0.1 mm and about 5 mm.

In other variations, for example, when the devices have a flat sidesurface (FIGS. 24A-24D) or a flat front or back surface (FIG. 22), theloading mechanism includes a loading dock located 180 degrees from theflat surface. This results in a loading dock pointing straight upwards,which enables its penetration into a drug container in the dependentposition, which in turn enables airless drug delivery into the device,as well as complete drug removal from the storage container and itsloading into the said device without drug retention and loss in thestorage container.

In further variations, as shown in FIGS. 33A-33B, an access port(loading port) (144) may be provided at the distal end of the needleassembly (125) that allows drug from a storage container (146) to beloaded into the reservoir (122). Access port (144) may be placed at anysuitable location on the needle assembly (125) or housing (102) toprovide access to the reservoir. For example, if desired, the accessport may be placed in the front wall (i.e., side or lateral wall) of thehousing or even the ocular contact surface (not shown) so that drugloading occurs from the front of the device. The lateral access port maybe configured to load drug through the wall of the device housing andinto the reservoir in a manner that directs the drug toward the plungerseal and away from the internal opening of the injection needle, oralong the surface of the plunger seal with an angle between 0 degrees(i.e., parallel to the seal surface) and about 70 degrees. This way thesmall amount of the medication to be loaded does not get splashed overthe front part of the drug reservoir. In some variations, the lateralaccess port is round or oval. When the access port is round, it may havea diameter ranging from between about 1.0 mm and 5.0 mm. The lateralaccess port may be positioned at about a 1 degree to about a 90 degreeangle with respect to the axis of the plunger. With this orientation,direct visualization of drug loading may occur while moving the plunger.In some variations, an injection device is configured to include aloading port at the front end of the device (e.g., distal end of thehousing) that extends through the side wall of the housing. The loadingport may or may not be near a side trigger. In other variations, theinjection device may be configured to include the combination of a sideloading port, a shielded needle, and a resistance component.

Access port (144) may comprise a seal or a plug configured to seal thereservoir against air or fluid leak, and/or external bacterialcontamination and may be made from any suitable material, e.g.,silicone, rubber, or any soft thermoplastic polymer such as, but notlimited to, polyurethane, Kraton™ styrenic block copolymers consistingof polystyrene blocks and rubber blocks, polyethylene, polypropylene,polyvinyl chloride, or combinations thereof that allows sealablepenetration by a sharp conduit.

In some variations, the access port stopper or seal may comprise a fullyor partially encircling sleeve. Here the sleeve may also serve as afinger grip or a holder. In another variation, and as shown in FIGS.52A-52C, the injection device (1400) may include an H-shaped stopper orplug (1402) for sealing the access port (1404) that provides accessthrough the housing wall (1406) of the device (1400) into the reservoir(1408). An opening (1410), e.g., in the wall of a needle assembly (1412)that contains the reservoir (1408), may be provided so that drug loadingmay occur through the access port (1404) and opening (1410) into thereservoir (1408). Here the H-shaped stopper or plug (1402) is flush withthe internal surface of the reservoir (1408) when it is inserted to sealthe access port (1404).

One or multiple membranes (148) may also be provided, e.g., in theocular contact surface (108) to seal the internal compartment of thehousing against air leak and/or external bacterial contamination. Forexample, the thickness of the membrane or the combined plurality ofmembranes may range from about 0.025 mm to about 5.0 mm, or range fromabout 0.1 mm to about 1 mm. One or multiple small apertures (150) mayalso be included in the wall of the housing (102) to help control airoutflow from the housing (102). The number and diameter of the apertures(150) may be varied to control the rate of (needle assembly and) needledeployment.

In some variations, e.g., when a pneumatic actuation mechanism is used,drug loading may be controlled by a drug-loading piston. For example, asshown in FIG. 38, the device (400) may include a drug-loading piston(402) having a proximal end (404) and a distal end (406). The distal end(406) is adapted to include a threaded portion (408). Thus, duringloading of a drug from container (410) through adaptor (412) and accessport (414), the drug-loading piston (402) can be rotated and withdrawnto create negative pressure within the reservoir (416). This negativepressure in turn draws the drug through the needle (418) and into thereservoir (416). A receptacle (420) may also be provided at the distalend of the device for holding initially loaded drug prior to transferinto the reservoir (416).

Some variations of the drug loading devices include a filter thatfilters the contents of the drug container as it is delivered into thereservoir. For example, the filter may be used to remove infectiousagents and enhance sterility of an active agent formulation beforedelivery into the reservoir. Thus, inclusion of a filter into the drugloader may be useful because the eye is an immune-privileged site, andintroduction of even a small quantity of pathogens such as bacteria maycause sight-threatening intraocular infection (endophthalmitis). Thefilter may also be used to remove impurities, e.g., silicone droplets,from an active agent formulation as it is transferred to the reservoirand prior to injection into the eye. This may be useful for intraoculardrugs because a small impurity injected into a subject's eye may resultin the subject seeing it as floater(s) that may be intractable, whichsignificantly worsens the quality of vision.

In one variation, the filter pore size is between about 0.2 μm (microns)and about 10 μm (microns) to facilitate filtration of bacterialpathogens from the outgoing drug being injected intraocularly. Inanother variation, the filter pore size is between about 0.1 μm(microns) and about 500 μm (microns) to facilitate filtration ofparticulate matter or impurities such as silicone droplets from theoutgoing drug being injected intraocularly. In yet a further variation,the filter pore size is between about 0.2 μm (microns) to about 4.0 μm(microns). Thickness of the said filter may range from between about 50μm (microns) to about 250 μm (microns), or from between about 10 μm(microns) to about 10000 μm (microns).

The filter may be made from any suitable non-reactive material, such asa low protein-binding material. Exemplary filter materials includewithout limitation, thermoplastic fluoropolymers such as PVDF(polyvinylidene fluoride); mixed cellulose esters; nylons; polyesters;nitrocelluloses; acrylic polymers such as Versapor® acrylic copolymer;polyethersulfones such as found in Supor™ filters; a combination, amixture, or a blend thereof.

The filter may be integrated with the drug loading device housing, thereservoir, a conduit, or any suitable part of the device. In anothervariation, filter is detachable or removable from the device. In onevariation, the filter is located within the reservoir at its distal end.In another variation, the filter is located at the proximal end of thelumen of the conduit. The filter may also be placed at any suitablelocation within and along the lumen of the conduit, e.g., at itsproximal end, in the middle, or at the distal end of the conduit.

Actuation Mechanisms

The devices described here generally include an actuation mechanismwithin the housing that deploys the conduit from the housing and enablesthe delivery of drug from the device into the intraocular space. Inother variations, the conduit is deployed by an actuation mechanismcontained within a separate cartridge that can be removably attached tothe device housing, e.g., using snap-fit or other interlocking elements.The actuation mechanisms may have any suitable configuration, so long asthey provide for accurate, atraumatic, and controlled delivery of druginto the intraocular space. For example, the actuation mechanisms maydeliver a drug or formulation into the eye by way of intraocularinjection at a rate ranging from about 1 μl/sec to about 1 ml/sec, fromabout 5 μl/sec to about 200 μl/sec, or from about 10 μl/sec to about 100μl/sec. The actuation mechanisms may generally provide a force of needledeployment that is strong enough to penetrate the eye wall comprisingthe conjunctiva, sclera and the pars plana region of the ciliary body,but less than that causing damage to the intraocular structures due tohigh velocity impact. This force depends on several physical factors,including but not limited to, the needle gauge utilized, the speed/rateof needle deployment at the point of contact between the needle tip andthe eye wall which in turn determines the impact force. An exemplaryrange of force that may be generated by the actuation mechanisms isabout 0.1 N (Newton) to about 1.0 N (Newton). The velocity of needledeployment may also range between about 0.05 seconds and about 5seconds.

In some variations, the actuation mechanism is a single-springmechanism. In other variations, the actuation mechanism is a two-springmechanism. In further variations, the actuation mechanism is pneumatic,e.g., employing negative pressure such as vacuum, or a positive pressuredriven mechanism. In further variations, the actuation mechanism isdriven magnetically or electrically, e.g., by a piezo-electric ormagnetic rail mechanism. These types of actuation mechanisms may beconfigured to allow independent control of the rate and force of druginjection (controlled, e.g., by the first spring member in thetwo-spring variation), and the rate and force of the dispensing memberdeployment (controlled, e.g., by the second spring member in thetwo-spring variation). Exemplary two-spring mechanisms are shown inFIGS. 26 and 27.

FIG. 28 also depicts an exemplary integrated intraocular drug deliverydevice with a two-spring actuation mechanism. In FIG. 28, the device(100) includes a housing (102) having a proximal end (104) and a distalend (106). An ocular contact surface (108) is attached to the distal end(106). A measuring component (110) is attached to one side of the ocularcontact surface (108). As further described below, a trigger (112) thatis operatively coupled to the housing (102) works with the first spring(114) and the second spring (116) of the actuation mechanism to deploypins (118) through openings (120) in the housing (102), to therebydeliver drug from the reservoir (122). First spring (114), second spring(116), pins (118), openings (120), and reservoir (122) are better shownin FIG. 29. Also in FIG. 29, a conduit, e.g., needle (124), is depictedwithin the housing in its first non-deployed state. Needle (124) isconfigured as being part of an assembly (125) such that movement of theassembly results in corresponding movement of the needle (124). A stop(115) is provided at the proximal end (127) of the assembly (125), whichis connected to the distal end of the first spring (114) and theproximal end of the second spring (116). The springs, as well as othercomponents of the device may be connected via medical grade adhesives,friction or snap fit, etc.

In FIG. 30, the second spring (116) is operatively connected to aplunger (132) by friction fit within a compartment (134) of the plunger(132). In the pre-activated state, as shown in FIG. 29, the plunger(132) and second spring (116) are held in place by pins (118). The pins(118) are removably engaged to the plunger (132) at plunger groove(138), and lock the plunger (132) in place via friction fit against theplunger groove (138) and housing (102).

Activation of the first spring (114) of the actuation mechanism byactivating the trigger deploys the needle (124) into the intraocularspace, i.e., it moves the needle (124) from its first non-deployed state(FIG. 29) to its second deployed state (FIG. 30). Referring to FIGS. 30and 31A-31C, activation of the first spring (114) occurs by depressionof trigger (112) by, e.g., one or two fingers, which also depressesbuttons (126). As shown in FIGS. 31A and 31B, buttons (126) areconfigured with a button groove (128) that allows the buttons (126) toalign with channels (130) in the housing (102). Once aligned with thechannels (130), the buttons (126) may be slidingly advanced along thechannels (130). The channels may be of any suitable length. The distancefrom the distal end of the channel to the distal end of the housing mayrange from about 10 to about 20 mm. In one variation, the distance fromthe distal end of the channel to the distal end of the housing is about16 mm. The rate of movement along the channels (130) may be controlledmanually by the user, automatically controlled by the force of springexpansion, or a combination of both. This movement of the buttons (126)allows expansion of the first spring (114) against stop (115) so thatthe needle assembly (125) and needle (124) can be deployed. The channelsin the housing may have any suitable configuration. For example, asshown in FIG. 31C, the channels (130) may be spiral cut within thehousing to allow rotation or a corkscrew type movement of the needleupon advancement, which may facilitate needle penetration through theeye wall.

Activation of the first spring (114) will typically result in activationof the second spring (116) to deliver drug out of the device and intothe intraocular space. For example, as shown in FIG. 30, the expansionforce of first spring (114) against stop (115) that is also connected tothe proximal end of the second spring (116) works to expand the secondspring (116) so that the assembly (125) is advanced within the housing(102). As illustrated in FIGS. 32A-32C, when the pins (118) that areremovably engaged to plunger (132) reach openings (120), they aredeployed out through the openings (120). Expulsion of the pins (118)from the device, then allows free expansion of the second spring (116)against plunger (132), to thereby push drug residing with reservoir(122) out of the device. The openings (120) may be covered by a membraneor seal (140) that can be penetrated by the pins (118) to give a visualindication that the drug has been delivered.

A two-spring actuation mechanism, as shown in FIGS. 41A-41B may also beused. Referring to FIG. 41A, integrated device (600) includes anactuation mechanism comprising a first spring (602) and a second spring(604). In use, when trigger (606), e.g., a lever, is depressed, firstspring (602) is released to advance shaft (608) in the direction of thearrow, which in turn advances needle (610) out of the tip of the device(600). Continued advancement of the shaft (608) advances the injectionsleeve (612) and top seal (614) so that drug within reservoir (616) maybe delivered through needle (610). Referring to FIG. 41B, once the drughas been injected, tabs (618) removably engage housing openings (620) tothereby release second spring (604), which then moves shaft (608)backward to retract needle (610) (not shown).

In some variations, a single-spring actuation mechanism is employed, asshown in FIGS. 36 and 37. When a single spring is used, the actuationmechanism is configured much like the two-spring mechanism describedabove except that the second spring is removed. Thus, in itspre-activated state, as shown in FIG. 36, a device (300) with a singlespring (302) may activate the single spring (302) by depression oftrigger (304) by, e.g., one or two fingers, which also depresses buttons(306). The buttons (306) are configured with a button groove (308) thatallows the buttons (306) to align with channels (not shown) in thehousing (310). Once aligned with the channels, the buttons (306) may beslidingly advanced along the channels. This movement of the buttons(306) allows expansion of the spring (302) against plunger (312) so thatthe needle assembly (314) and needle (316) can be deployed. When thepins (318) that are removably engaged to plunger (312) reach openings(320) within the housing (310), they are deployed out through theopenings (320). Expulsion of the pins (318) from the device, then allowsfurther expansion of the spring (302) against plunger (312), to therebypush drug residing with reservoir (322) out of the device. Although notshown here, the openings (320) may be covered by a membrane or seal thatcan be penetrated by the pins (318) to give a visual indication that thedrug has been delivered.

A pneumatic actuation mechanism may also be employed. In one variation,as depicted in FIGS. 34 and 35A and 35B, the pneumatic actuationmechanism includes a plunger, pins, and housing openings in the samefashion as described for the single- and two-spring mechanisms. However,instead of using a spring to deploy the needle assembly and plunger, apiston is used to slidingly advance the needle assembly within thehousing. For example, in FIG. 34, a device with a pneumatic actuationmechanism (200) includes a piston (202) and trigger (204). The piston(202) is used to compress air into the housing (206) of the device(202). If desired, the amount of compressed air the piston includes inthe device may be controlled by a dial or other mechanism (not shown).The proximal end of the housing may also be configured, e.g., with aflange, crimps, or other containment structure, that allowstranslational movement of the piston (202) into the housing but not outof the housing. Upon depression of a trigger (208), a pair of lockingpins (210) are also depressed to thereby allow the compressed airgenerated by the piston (202) to push the needle assembly (212) forward.This advancement of the needle assembly (212) deploys the needle (214)out of the device (FIG. 35B). As previously stated, pins (216) similarto those above that lock the plunger (218) in place are also provided.Upon their expulsion from the device out of openings (220) in thehousing (206) due to forward movement of the needle assembly (212), thecompressed air further moves the plunger (218) forward to thereby pushdrug residing with reservoir (222) out of the device. Rotational pins(224) may also be included, which upon release by the sliding needleassembly (212) allow rotation of the needle assembly (212) with respectto the housing (206).

As previously stated, a trigger may be coupled to the housing andconfigured to activate the actuation mechanism. In one variation, thetrigger is located on the side of the device housing proximate thedevice tip at the ocular interface surface (e.g., the distance betweenthe trigger and device tip may range between 5 mm to 50 mm, between 10mm to 25 mm, or between 15 mm to 20 mm), so that the trigger can beactivated by a fingertip while the device is positioned over the desiredocular surface site with the fingers on the same hand. In anothervariation, the trigger is located on the side of the device housing at90 degrees to the measuring component, so that when the ocular contactsurface is placed on the eye surface perpendicular to the limbus, thetrigger can be activated with the tip of the second or third finger ofthe same hand that positions the device on the ocular surface.

Some variations of the device may include a control lever for initiatingplunger movement. In these instances, the control lever may actuate theplunger in a mechanical manner, e.g., by spring-actuation, similar tothat described above. In other variations, actuation of the plunger mayoccur through a combination of mechanical and manual features. Forexample, the initiation of plunger movement may be aided by a manualforce applied onto the control lever, while a spring-actuated mechanismfor generating a mechanical force is also employed to move the plungerforward inside the device barrel to inject drug. In instances where thecontrol lever is connected to the plunger, the initiation of plungermovement and drug injection is controlled by the manual component,whereas the rate of fluid injection is controlled by the mechanicalforce. Here a reduced manual force may be applied to the plunger due toits combination with a co-directional mechanical force, thusfacilitating the stability of device positioning on the ocular surfaceat a precise injection site.

The control lever may be placed between 10 mm and 50 mm from the tip ofthe device that interfaces with the eye surface, or between 20 mm and 40mm from the tip of the device. Positioning of the control lever in thismanner may enable atraumatic and precise operation of the device withone hand.

As illustrated in FIGS. 43A-43D, exemplary integrated device (700)includes a housing (702), a dynamic sleeve (704) slidable thereon, anocular contact surface (706), a plunger (708), and a control lever (710)for manually actuating the plunger (708) to inject drug through needle(712). An expanded sectional view of the ocular contact surface (706),dynamic sleeve (706), plunger (708), and needle (712) shown in FIG. 43 Ais shown in FIG. 43B. In use, after placing the ocular contact surface(706) on the eye, the applied pressure may automatically slide thedynamic sleeve (704) back (in the direction of the arrow) to expose theneedle and allow needle penetration through the eye wall. The controllever (710) may then be slidably advanced manually (in the direction ofthe arrow in FIG. 43C) to advance plunger (708). When injection of thedrug through the needle (712) is complete, the dynamic sleeve (704) maybe slidably advanced manually to cover the needle, as shown in FIG. 43D.

The dynamic sleeve may be slidably advanced or retracted manually by afine mobility control mechanism, also referred to as a mobility controlmechanism. In these instances, the dynamic sleeve may comprise ahigh-traction surface located on the outer surface of the sleeve, whichmay aid movement of the sleeve with a fingertip. In one variation, thehigh-traction surface may be engraved or contain markings with aserrated pattern. In other variations, as shown in FIG. 45A, a platformor pad (e.g., a fingertip pad) (900) may be attached to the outersurface of the sleeve (902) to help manually advance or retract thesleeve. The platform or pad may also include a high-traction surface(904), the perspective, side, and top views of which are illustrated inFIGS. 45B, 45C, and 45D, respectively. Platform or pad (900) willtypically include a base (912) for attachment to the sleeve (902). Base(912) may be of any suitable configuration. For example, the base of theplatform or pad may be configured as a cylinder (FIG. 45H) or with anarrowed portion (portion of lesser diameter), such as a dumbbell orapple core shape (FIG. 45I). In yet further variations, the finemobility control mechanism is configured as raised, circular flangelocated at or near the proximal edge of the dynamic sleeve. In oneexample, the circular flange is raised about 1 mm to about 1.5 mm overthe outer surface of the dynamic sleeve, so that the operator has atactile feel of its surface, and is able to control movement of thesleeve when applying a retractive (pulling) or pushing force to it.

Some variations of the devices described herein include a grip having aretraction slot or channel that works in combination with the dynamicresistance component to inject drug into the eye. Referring to FIG. 45A, grip (906) may be a component coupled (usually fixedly attached) tothe device housing (908) at the proximal end (912) of the sleeve (902).The grip (906) may be configured to include a retraction slot (910) inits wall. In use, when the sleeve (902) is retracted, as shown by thedirection of the arrow in FIG. 45J, the base (912) of the pad orplatform is moved into the slot (910). The retraction slot (910) may beconfigured as a channel of uniform width (FIG. 45F), or as a channelwith a keyhole-type configuration, e.g., having a narrowed portion (FIG.45G) or enlarged portion (FIG. 45E) at the slot proximal or distal end.The retraction slot may provide sensory feedback, e.g., when theendpoint of retraction is reached. The configuration of the base of theplatform or pad may be chosen so that it provides a friction fit withthe slot. For example, when the slot has a narrowed portion, the basemay also have a narrowed portion.

When grips are employed, the devices may also include a lockingmechanism. In one variation, when the end point of the sleeve retractionand needle exposure/deployment is reached, the wide portion of thesleeve slot is aligned with the wide portion of a grip slot and with anopening in the housing and an opening in the plunger shaft, allowing theplatform base to be inserted into the plunger shaft to lock it relativeto the platform that become an actuation lever for manual druginjection. The narrow part of the base enters the narrow part of thesleeve slot, which unlocks the platform relative to the sleeve allowingits movement towards device tip. In another variation, when the platformbase reaches the end point of the retraction slot, it may be depressedinto an opening in the plunger shaft and becomes a locking pin toconnect the platform and the plunger. When it is depressed, its narrowportion enters the keyhole-shaped slot in the sleeve, and becomesmovable within the slot moving towards the tip of the sleeve (unlocksthe platform base and sleeve).

The mobility control mechanism may be beneficial when the user desiresto control the amount of pressure exerted by the device tip on the eyesurface in order to deploy the needle during its intraocularpenetration. With a mobility control mechanism, the user may use afingertip to either reduce or increase counter-forces that regulate thesleeve movement and needle exposure.

For example, if the user exerts the pulling force onto the saidhigh-traction surface (that is pulling the high-traction surface of thesleeve away from the device tip), this movement may facilitate needleexposure and reduce the amount of pressure force (down to 0 Newton)needed to be applied to the eye wall in order to slide the sleeve backand expose the needle. In another variation, if the user exerts apushing force (that is pushing the high-traction surface of the sleevetowards the device tip), this movement may counteract and impedes needleexposure, which may allow the device tip to apply increased pressure tothe eye wall prior to the initiation of sleeve movement and needleexposure.

In use, the platform or pad may be slid with a second or third finger.Again, this allows the injector to manually modulate the sleeveresistance and movement along the device tip. For example, by pushingthe pad and thus the sleeve forward with a fingertip, the injectorprovides some resistance at the beginning of the procedure when thedevice tip is being positioned on the eye surface (and the needle needsto remain completely covered). Then the injector would release his/herfingertip from the sleeve pad to enable needle deployment and itstransscleral penetration. Some variations of the device may also includea step or a ring-shaped ridge at the end of the sleeve path, so thatafter the sleeve is pulled back past this step, it would automaticallytrigger spring-actuated plunger movement. The fingertip pad could beused to pull the sleeve back past the said step at the end of needledeployment in order to actuate the plunger movement and drug injection.

When a platform or pad is employed, it may reduce the amount of pressurethe device exerts on the eyeball before the sleeve begins to move toexpose the needle, and thus, allow customization of the amount ofapplied pressure from patient to patient.

In another aspect, the dynamic sleeve may provide gradual needleexposure as it penetrates through the eye wall so that the needle isexposed 1 mm or less when it meets most resistance at the eye surface.Here the rest of the needle is located inside the sleeve with at leastits most distal unexposed point or a longer segment being protectedinside the narrow exit orifice or canal. Such sleeve design may minimizethe risk of needle bending compared to the conventional syringe with along exposed needle. This design may enable the utilization of smaller agauge needle without increased risk of it being bent as it penetratedthrough the eye wall. The smaller needle gauge may render it morecomfortable and less traumatic during its intraocular penetration.

Some variations of the devices described here may comprise an endpointshock absorber. The endpoint shock absorber may be a component thatcushions the eye against the force transmitted by the dynamic sleeve andthe needle when they come to an abrupt stop. The transmitted force wavemay be harmful for the delicate structures inside the eye such as thelens, retina and the choroidal vasculature. Inclusion of an endpointshock absorber may allow the needle to come to a soft and gradual stopat the end of its deployment path when it is fully extended through theeye wall into the intraocular cavity. In one variation, the shockabsorber is provided as a tapered surface at the distal end or distalportion of the dynamic sleeve. In another variation, the shock absorberis a soft sleeve located at the base of the drug conduit (such as at thehub of an injection needle). Here the soft sleeve may be configured tocontact the tip of the device when the needle is fully deployed. In yetanother variation, the shock absorber is the soft tip of the device,where the soft tip is configured to contact the hub of the needle whenthe needle is fully deployed. Exemplary materials suitable to make theendpoint shock absorbers include without limitation, methylmethacrylate(MMA); polymethylmethacrylate (PMMA); polyethylmethacrylate (PEM) andother acrylic-based polymers; polyolefins such as polypropylene andpolyethylene, vinyl acetates, polyvinylchlorides, polyurethanes,polyvinylpyrollidones, 2-pyrrolidones, polyacrylonitrile butadiene,polycarbonates, polyamides, fluoropolymers such aspolytetrafluoroethylene (e.g., TEFLON™ polymer); polystyrenes; styreneacrylonitriles; cellulose acetate; acrylonitrile butadiene styrene;polymethylpentene; polysulfones; polyesters; polyimides; natural rubber;polyisobutylene rubber; polymethylstyrene; silicone; and derivatives,copolymers and blends thereof.

The devices described herein may also include a visual feedbackmechanism or a needle deployment indicator configured to allow theoperator to precisely determine when the needle has been deployed to thedesired extent, and to safely initiate drug injection. Furthermore,during the needle deployment process, the eyes of the operator should bepointed at or near the device tip-eye interface. Thus, it would bebeneficial for the visual feedback mechanism to be located in closeproximity to the device tip-eye interface, so as not to distract theoperator from closely monitoring the device position during the entireintraocular drug delivery procedure. With such a configuration, theoperator does not have to take his/her eyes off of the device-ocularinterface during the entire injection procedure, minimizing the risk ofaccidental trauma during unexpected movement of the eye or head of thesubject. In some variations, the visual feedback mechanism may becoupled to a mechanical stopper at the end-point of the needledeployment process. Here the visual feedback mechanism may be configuredas an elongated measuring tip band, where the tip comes up to a stopagainst the needle base or hub, which determines the end-point of needledeployment when the sleeve has been fully retracted. In one variation,the needle base and/or the distal end of the needle hub is colored in ahigh-visibility dye, such as black, that could be directly visualizedthrough a transparent or translucent material of the slidable shield.Another example of the visual feedback mechanism is a band or a spacerplaced on the needle base, so that the band comes up to a stop againstthe inside surface of the tip, which determines the end-point of needledeployment when the sleeve has been fully retracted.

An exemplary injection device is shown in FIG. 48. In the figure,injection device (1100) comprises a housing (1101) having a wall (1106),a proximal end (1102), a distal end (1104), and a lumen (not shown)extending between the proximal end (1102) and distal end (1104). Aplunger (1108) is slidable at least partially through the lumen. Alongitudinally extending channel (1110) having a proximal end (1109) anda distal end (1111) formed through the wall (1106) is provided at thedevice distal end (1104). A plunger actuation lever such as knob (1112)is configured so that slidable advancement of the knob (1112) from thechannel proximal end (1109) to the channel distal end (1111) alsoslidably advances the plunger (1108) to deliver medication into the eye.The channels may be of any suitable length. The distance from the distalend of the channel (1111) to the distal end of the housing (1104) mayrange from about 10 to about 20 mm. In FIG. 48, the distance from thedistal end of the channel (1111) to the distal end of the housing (1104)is about 16 mm. The injection device of FIG. 48 also includes a cover orsleeve (1114) that overlays an opening or aperture in the housing wall(not shown) through which a drug loader (as previously described) may beplaced. The drug loader would deliver medication from a drug vial to thereservoir of the device. The cover or sleeve (1114) may partially,substantially or entirely surround the housing and be made frommaterials such as rubber or silicone. The drug loader may puncture thecover or sleeve and extend through the opening or aperture of thehousing so that medication can be filled into the reservoir.

In FIG. 48, the injection device also includes a flange (1116). Aspreviously described, flange (1116) may be part of a fine mobilitycontrol mechanism. The flange (1116) may be configured as a raised,circular flange located at or near the proximal edge of a dynamic sleeve(1118). As shown in more detail in FIG. 49B, dynamic sleeve (1118) has afirst section (1120) and a second section (1122). The inner diameter offirst section (1120) will typically be greater than the inner diameterof second section (1122). For example, the inner diameter of the firstsection may be about 7.0 mm and the inner diameter of the second sectionmay be about 4.8 mm. The length of the first and second sections mayalso vary. In FIG. 49B, the length of the first section (1120) may beabout 9.0 to 10 mm and the length of the second section (1122) may beabout 9.0 to 10 mm. A ramped portion (1124) may also connect the firstand second portions (1120 and 1122). Ramped portion (1124) may beconfigured so that an angle is created with the longitudinal axis (1126)of the device, e.g., an angle of 30 degrees as shown in FIG. 49B.

The injection device of FIG. 48 also includes a sectoral measuringcomponent (1128). The sectoral measuring component in this as well asother variations has a circumference (that spans 360 degrees) and alongitudinal axis. Radially extending members such as tabs or spokes maybe provided around the circumference of the sectoral measuring componentin any suitable manner, e.g., equidistant from each other, symmetricallyor asymmetrically spaced around the circumference, but typically in amanner that avoids contact with the eyelid(s) and eyelashes to maintainits sterility. Thus, the radially extending members will generally beprovided on a section (portion) of the circumference and will generallyspan a certain number of degrees of arc around the circumference. Forexample, and as specifically shown in FIG. 50, sectoral measuringcomponent (1200) has a section (1202) having three radially extendingmembers (1204). The section (1202) spans an area (e.g., arc) around thecircumference of 90 degrees. In this configuration, the radiallyextending members are spaced around the circumference 45 degrees apartfrom each other. In another variation, as shown in FIG. 51, sectoralmeasuring component (1300) is configured similarly to that illustratedin FIG. 50 except that the distal ends of the radially extending members(1302) are rounded.

Referring to FIGS. 58A-58C, a further variation of an exemplary oculardrug delivery system/injection device is shown. In FIG. 58A, theinjection device (2000) includes a cover (2002), a housing (e.g., asyringe barrel) (2004), a plunger (2006), and a domed actuator (2008)that is slidable within slot (2010) in the housing wall, and which iscoupled to the plunger (2006) to deliver drug out of the device. Thesystem is broken down to show its various components in more detail inFIG. 58B. In FIG. 58B, the cover (2002), housing (2004), plunger (2004),and domed actuator (2008) are shown. The cover may be made from anysuitable material. Exemplary materials include without limitation,polyethylene, polycarbonate, polypropylene, acrylonitrile butadienestyrene polymers, Delrin® acetal homopolymers, polyurethane, acrylicpolymers, polyether ether ketone, and combinations thereof. In onevariation, the cover is made from polycarbonate. Further depicted are aseal (2012) at the distal end (2014) of the plunger (2006) and a screwor pin (2016) for fixing the domed actuator (2008) to the plunger(2006). A needle hub assembly (2018) is also shown having an attached 30gauge needle (2020), projections (2022), and a ring (2024). However, itis understood that the needle hub assembly may include any suitablysized needle. The system further includes a slidable shield (2026). Aspreviously described, movement of the shield (2026) along theprojections in the proximal direction (direction of the arrow) createsresistance until the shield (2026) is stopped by ring (2024). In thisvariation, a filter assembly comprising a filter capture ring (2028), aPTFE filter disk (2030), and a mesh backer (2032) are provided in theneedle hub (2018). It is understood that the needle hub (2018) can beremovably attached to, or fixed to, the housing (2004). An ocularmeasuring component (2034) and needle stabilization mechanism, tunnel(2035) is also provided in this variation. In FIG. 58C, an enlarged viewof the domed actuator (2008) is depicted. The domed actuator (2008)includes ridges (2036) to aid the grip and or manipulation of theactuator (2008) by the user.

II. Methods

Methods for using the intraocular drug delivery devices are alsodescribed herein. In general, the methods include the steps ofpositioning an ocular contact surface of the device on the surface of aneye, applying pressure against the surface of the eye at a targetinjection site using the ocular contact surface, and delivering anactive agent from the reservoir of the device into the eye by activatingan actuation mechanism. The steps of positioning, applying, anddelivering are typically completed with one hand.

The methods may also include placing an ocular contact surface of aninjection device against the eye wall, generating variable resistance toconduit advancement as the conduit is deployed through the eye wall,removing air from the composition before the composition is deliveredinto the eye by passing the composition through an air removalmechanism, and injecting the composition into the eye.

In some instances, the method may include coupling an injectorattachment to a syringe body, the injector attachment comprising avariable resistance component, an air removal mechanism, an ocularcontact surface, and a needle, and the syringe body having a proximalend and a distal end, and a reservoir for containing a compositiontherein; placing the ocular contact surface of the injector attachmentagainst the eye wall; generating variable resistance to needleadvancement as the needle is deployed through the eye wall; removing airfrom the composition before the composition is delivered into the eye bypassing the composition through the air removal mechanism; and injectingthe composition into the eye.

In addition to removing air, the method may further comprise the step ofremoving bacteria or particulates from the composition before thecomposition is delivered into the eye, the step of limiting theinjection force of the composition, and/or the step of limiting thedistance the composition travels in the eye when the composition isinjected. When the distance of composition travel in the eye is limited,the distance may be limited to between about 5 mm and about 25 mm,between about 5 mm to about 20 mm, between about 5 mm and about 15 mm,or between about 5 mm to about 10 mm. As previously stated, the removalof air from the composition before it is delivered into the eye may beparticularly beneficial when a viscous composition, e.g., a compositioncomprising ranibizumab, is injected.

The application of pressure against the surface of the eye using theocular contact surface may also be used to generate an intraocularpressure ranging between 15 mm Hg to 120 mm Hg, between 20 mm Hg to 90mm Hg, or between 25 mm Hg to 60 mm Hg. As previously stated, thegeneration of intraocular pressure before deployment of the dispensingmember (conduit) may reduce scleral pliability, which in turn mayfacilitate the penetration of the conduit through the sclera, decreaseany unpleasant sensation on the eye surface during an injectionprocedure, and/or prevent backlash of the device. Intraocular pressurecontrol may be generated or maintained manually or automatically usingpressure relief valves, pressure sensors, pressure accumulators,pressure sensors, or components such as slidable caps having lockingmechanisms and/or ridges as previously described.

Use of the devices according to the described methods may reduce painassociated with needle penetration through the various covers of the eyewall such as the conjunctiva that is richly innervated with pain nerveendings. The anesthetic effect at the injection site during anintraocular injection procedure may be provided by applying mechanicalpressure on the conjunctiva and the eye wall over the injection sitebefore and/or during the needle injection. The application of mechanicalpressure to the eye wall may also transiently increase intraocularpressure and increase firmness of the eye wall (and decrease itselasticity), thereby facilitating needle penetration through the sclera.Furthermore, the application of mechanical pressure to the eye wall maydisplace intraocular fluid within the eye to create a potential spacefor the drug injected by the device.

The devices may be used to treat any suitable ocular condition.Exemplary ocular conditions include without limitation, any type ofretinal or macular edema as well as diseases associated with retinal ormacular edema, e.g., age-related macular degeneration, diabetic macularedema, cystoid macular edema, and post-operative macular edema; retinalvascular occlusive diseases such as CRVO (central retinal veinocclusion), BRVO (branch retinal vein occlusion), CRAO (central retinalartery occlusion), BRAO (branch retinal artery occlusion), and ROP(retinopathy of prematurity), neovascular glaucoma; uveitis; centralserous chorioretinopathy; and diabetic retinopathy.

When dexamethasone sodium phosphate solution is used to treat an ocularcondition, the dose of dexamethasone sodium phosphate that may beadministered into the eye by each individual injection device may rangebetween about 0.05 mg and about 5.0 mg, between about 0.1 mg and about2.0 mg, or between about 0.4 mg and about 1.2 mg.

In some variations, a topical anesthetic agent is applied on the ocularsurface before placement of the device on the eye. Any suitable topicalanesthetic agent may be used. Exemplary topical anesthetic agentsinclude without limitation, lidocaine, proparacaine, prilocalne,tetracaine, betacaine, benzocaine, bupivacaine, ELA-Max®, EMLA®(eutectic mixture of local anesthetics), and combinations thereof. Inone variation, the topical anesthetic agent comprises lidocaine. Whenlidocaine is used, it may be provided in a concentration raging fromabout 1% to about 10%, from about 1.5% to about 7%, or from about 2% toabout 5%. In another variation, the topical anesthetic agent is mixedwith phenylephrine or another agent that potentiates or/and prolongs theanesthetic effect of the pharmaceutical formulation. The topicalanesthetic agent may be provided in any suitable form. For example, itmay be provided as a solution, gel, ointment, etc.

An antiseptic agent may also be applied on the ocular surface beforeplacement of the device on the eye. An antiseptic agent may also beapplied to the device tip before placement of the device on the eye.Examples of suitable antiseptic agents include, but are not limited to,iodine, iodine-containing combinations, povidone-iodine (Betadine®),chlorhexidine, soap, antibiotics, salts and derivatives thereof, andcombinations thereof. The antiseptic agent may or may not be applied incombination with a topical anesthetic agent. When the antisepticcomprises povidone-iodine (Betadine®), the concentration ofpovidone-iodine may range from about 1% to about 10%, from about 2.5% toabout 7.5%, or from about 4% to about 6%.

During the drug delivery process, the devices described here may beconfigured so that the injection needle enters the eye at the rightangle that is perpendicular to the eye wall (sclera). In otherinstances, the device may be configured so that the injection needleenters through the cornea into the anterior chamber of the eye parallelto the iris plane.

III. Systems and Kits

Systems and kits that include the intraocular drug delivery devicesdisclosed herein are also provided. The kits may include one or moreintegrated drug delivery devices, one or more injection devices, one ormore conventional syringes, and/or one or more removably couplableinjector attachments. The devices may be preloaded with an active agent.When a plurality of preloaded devices are included, they may beseparately packaged and contain the same active agent or differentactive agents, and contain the same dose or different doses of theactive agent.

The systems and kits may also include one or more separately packageddevices (or conventional syringes) that are to be manually loaded. Ifthe devices are to be manually loaded prior to use, then one or moreseparately packaged active agents may be incorporated into the kit.Similar to the preloaded device system or kit, the separately packagedactive agents in the systems and kits here may be the same or different,and the dose provided by each separately packaged active agent may bethe same or different.

Of course, the systems and kits may include any combination of preloadeddevices, devices (or conventional syringes) for manual loading, andactive agents. It should also be understood that instructions for use ofthe devices will also be included. In some variations, one or moreseparately packaged measuring components may be provided in the systemsand kits for removable attachment to the devices. Topical anestheticagents and/or antiseptic agents may also be included.

In some variations of the systems and kits, the pharmaceuticalformulation is substantially non-irritating to the ocular surface. Thepharmaceutical formulation is generally sterile. In one example, thepharmaceutical formulation comprises an antiseptic. In another example,the antiseptic is detergent-free. In yet another example, the antisepticis in a single-use container. Examples of suitable antiseptic agentsinclude, but are not limited to, iodine, iodine-containing combination,povidone-iodine (Betadine®), chlorhexidine, soap, antibiotics, salts andderivatives thereof, and combinations thereof.

When the antiseptic comprises povidone-iodine (Betadine®), theconcentration of povidone-iodine may range from about 1% to about 10%,from about 2.5% to about 7.5%, or from about 4% to about 6%. It may beuseful for the concentration of povidone-iodine to be about 5%. Theantiseptic formulation may be provided in forms that include, but arenot limited to, a solution, an antiseptic-soaked swab, or a single-usereservoir suitable for ophthalmic use.

In other variations, the pharmaceutical formulation comprises ananesthetic agent that is substantially non-irritating to the ocularsurface. Here the pharmaceutical formulation may contain both anantiseptic and an anesthetic agent. In other instances, the system/kitmay include two separately packaged pharmaceutical formulations, whereone formulation contains the antiseptic agent and the other separatelypackaged formulation contains the anesthetic agent. Examples ofanesthetic agents include, but are not limited to, lidocaine,tetracaine. The anesthetic formulation may be provided in forms such as,but not limited to, a solution, a gel, or a anesthetic-soaked swab orspongiform material, or a single-use reservoir suitable for ophthalmicuse. The antiseptic agent may or may not be applied in combination witha topical anesthetic agent.

The pharmaceutical formulation may be housed in a container, where thecontainer is integrated with the intravitreal drug injector housing,tip, drug reservoir, or any other suitable part. Alternatively, thecontainer may be configured to detach from the intravitreal druginjector. In one example, the container is hollow reservoir, ordrug-soaked spongeform material. In another example, the container isdisposable and packaged for a single-use. In yet a further example, thecontainer is sterile.

A pharmaceutical formulation may be applied on the ocular surface beforeplacement of the device on the eye. A pharmaceutical formulation mayalso be applied on the ocular contact surface of the device tip beforeplacement of the device on the eye. For example, an antiseptic may beapplied on the ocular surface before placement of the device on the eye.In another example, an antiseptic may also be applied on the ocularcontact surface of the device tip before placement of the device on theeye. In one variation, a physician may apply 5%povidone-iodine-containing pharmaceutical formulation onto the devicetip prior to placing the device onto the eye surface in order to ensuresterility of the injection site.

The systems or kits for intravitreal drug delivery may comprise anintegrated filter-containing drug conduit, or filter-containing drugreservoir, or a filter-containing adapter for transferring and/orloading a drug from a storage container into the intravitreal injectiondevices described herein. In one example, the filter is a hydrophilicmembrane. In another example, the filter's pore size is less than 4microns, or less than 0.4 microns, or between 0.1 microns and 0.4microns. In another example, the filter sterilizes a drug solution, forexample, by size-exclusion filtration. Such a filter may removebacterial pathogens. In another example, the filter removes fungalpathogens. In yet another example, the filter collectively removesbacterial, fungal and certain other pathogens.

This application further discloses the following variations 1-41, andany combination thereof:

Variation 1. An injector attachment for connection to an injectiondevice housing comprising: a needle assembly, the needle assembly havinga proximal end and a distal end; a resistance component; and an ocularcontact surface.

Variation 2. The injector attachment of variation 1, wherein theresistance component comprises a slidable sleeve.

Variation 3. The injector attachment of variation 1, wherein theresistance component comprises a lever.

Variation 4. The injector attachment of variation 3, wherein the leverreleasably secures a slidable sleeve.

Variation 5. The injector attachment of variation 3, wherein the leveris fixedly attached to the needle assembly.

Variation 6. The injector attachment of variation 3, wherein the leveris releasably attached to the needle assembly.

Variation 7. The injector attachment of variation 1, wherein the ocularcontact surface comprises a measuring component.

Variation 8. The injector attachment of variation 1, wherein themeasuring component comprises a plurality of radially extending members.

Variation 9. The injector attachment of variation 8, wherein theplurality of radially extending members are disposed 360 degrees aboutthe circumference of the measuring component.

Variation 10. The injector attachment of variation 2, wherein theslidable sleeve is rigid.

Variation 11. The injector attachment of variation 2, wherein theslidable sleeve is non-deformable.

Variation 12. The injector attachment of variation 1, wherein the needleassembly further comprises a needle stabilization mechanism.

Variation 13. The injector attachment of variation 1, wherein the needleassembly further comprises one or more filters.

Variation 14. The injector attachment of variation 1, wherein the needleassembly further comprises a hydrophilic filter.

Variation 15. The injector attachment of variation 14, wherein theneedle assembly further comprises a hydrophobic filter.

Variation 16. The injector attachment of variation 1, further comprisinga needle deployment indicator.

Variation 17. The injector attachment of variation 16, wherein theneedle deployment indicator comprises a high visibility dye.

Variation 18. A system for delivering a pharmaceutical formulation intothe eye comprising: the injector attachment of variation 1; a housing;and a drug reservoir disposed within the housing.

Variation 19. The system of variation 18, wherein the housing comprisesa syringe.

Variation 20. The system of variation 18, wherein the housing has aproximal end, a distal end, and a side wall, and comprises an actuationmechanism for delivering an active agent into an eye, wherein theactuation mechanism comprises a plunger.

Variation 21. The system of variation 20, wherein the actuationmechanism comprises a plunger actuation lever fixedly attached to theplunger and extending through the side wall of the housing.

Variation 22. The system of variation 21, wherein the actuationmechanism further comprises a back plunger.

Variation 23. The system of variation 18, further comprising an activeagent contained within the drug reservoir.

Variation 24. The system of variation 23, wherein the active agentcomprises an anti-VEGF agent selected from the group consisting ofranibizumab, bevacizumab, aflibercept, and modifications, derivatives,and analogs thereof, and combinations thereof.

Variation 25. The system of variation 24, wherein the active agentcomprises ranibizumab or bevacizumab.

Variation 26. The system of variation 23, wherein the active agentcomprises aflibercept, ocriplasmin, a steroid, ranibizumab, bevacizumab,a placenta-derived growth factor, a platelet-derived growth factor, orcombinations thereof.

Variation 27. The system of variation 23, wherein the active agentcomprises an anti-complement agent.

Variation 28. A method for injecting a pharmaceutical formulation intothe eye comprising: coupling an injector attachment to a syringe havinga proximal end and a distal end, the injector attachment comprising aneedle assembly having a needle, and a resistance component: generatinga resistive force with the resistance component; advancing the needlethrough the eye wall; and injecting the pharmaceutical formulation intothe eye.

Variation 29. The method of variation 28, wherein the resistive force isbetween 0 N and about 2 N.

Variation 30. The method of variation 29, wherein the resistive force isbetween about 0.05 N and about 0.5 N.

Variation 31. The method of variation 28, wherein the resistancecomponent comprises a slidable sleeve.

Variation 32. The method of variation 28, wherein the resistancecomponent comprises a lever having a locked configuration and anunlocked configuration.

Variation 33. The method of variation 32, wherein depression of one sidethe lever places the lever in its unlocked configuration.

Variation 34. The method of variation 28, wherein the needle assemblyfurther comprises a needle stabilization mechanism.

Variation 35. The method of variation 28, wherein the pharmaceuticalformulation is preloaded in the syringe.

Variation 36. The method of variation 28, wherein the pharmaceuticalformulation is loaded into the syringe immediately prior to its use.

Variation 37. The method of variation 30, wherein the pharmaceuticalformulation comprises an active agent.

Variation 38. The method of variation 37, wherein the active agentcomprises an anti-VEGF agent selected from the group consisting ofranibizumab, bevacizumab, aflibercept, and modifications, derivatives,and analogs thereof, and combinations thereof.

Variation 39. The method of variation 38, wherein the active agentcomprises ranibizumab or bevacizumab.

Variation 40. The method of variation 37, wherein the active agentcomprises aflibercept, ocriplasmin, a steroid, ranibizumab, bevacizumab,a placenta-derived growth factor, a platelet-derived growth factor, orcombinations thereof.

Variation 41. The method of variation 37, wherein the active agentcomprises an anti-complement agent.

This application also discloses the following variations 1″-50″, and anycombination thereof:

Variation 1″. An injector device for drug delivery comprising: a needleassembly, the needle assembly comprising a drug conduit; a measuringcomponent; and a priming-enabling component.

Variation 2″. The injector device of variation 1″, wherein the needleassembly is configured to removably attach to a drug reservoir.

Variation 3″. The injector device of variation 1″, wherein the needleassembly is configured to removably attach to a drug reservoir through aluer connector.

Variation 4″. The injector device of variation 3″, wherein the luerconnector comprises an internal luer seal.

Variation 5″. The injector device of variation 4″, wherein the internalluer seal comprises a proximal extension of the drug conduit and isconfigured to open into a drug reservoir.

Variation 6″. The injector device of variation 1″, further comprising aresistance component.

Variation 7″. The injector device of variation 6″, wherein theresistance component comprises a slidable sleeve.

Variation 8″. The injector device of variation 6″, wherein theresistance component comprises a lever.

Variation 9″. The injector device of variation 8″, wherein the leverreleasably secures a slidable sleeve.

Variation 10″. The injector device of variation 8″, wherein the lever isfixedly attached to the injector device.

Variation 11″. The injector device of variation 8″, wherein the lever isreleasably attached to the injector device.

Variation 12″. The injector device of variation 8″, wherein the levercomprises a flexible arm connector.

Variation 13″. The injector device of variation 12″, wherein the leverhas a biased position.

Variation 14″. The injector device of variation 12″, wherein the leverhas a locked position.

Variation 15″. The injector device of variation 1″, wherein themeasuring component comprises an ocular contact surface.

Variation 16″. The injector device of variation 1″, wherein themeasuring component comprises a plurality of radially extending members.

Variation 17″. The injector device of variation 16″, wherein theplurality of radially extending members are disposed between 45 degreesand 360 degrees about the circumference of the measuring component.

Variation 18″. The injector device of variation 7″, wherein the slidablesleeve is rigid.

Variation 19″. The injector device of variation 7″, wherein the slidablesleeve is non-deformable.

Variation 20″. The injector device of variation 1″, wherein the needleassembly further comprises a needle stabilization mechanism.

Variation 21″. The injector device of variation 1″, wherein thepriming-enabling component comprises a step-wise tunnel.

Variation 22″. The injector device of variation 1″, wherein thepriming-enabling component comprises at least two segments, each segmenthaving a different internal diameter.

Variation 23″. The injector device of variation 1″, wherein the needleassembly comprises one or more filters.

Variation 24″. The injector device of variation 1″, wherein the needleassembly comprises a hydrophilic filter.

Variation 25″. The injector device of variation 24″, wherein the needleassembly further comprises a hydrophobic filter.

Variation 26″. The injector device of variation 1″, further comprising aneedle deployment indicator.

Variation 27″. The injector device of variation 26″, wherein the needledeployment indicator comprises a high visibility dye.

Variation 28″. The injector device of variation 23″, wherein the one ormore filters comprises a sterilizing filter.

Variation 29″. The injector device of variation 28″, wherein thesterilizing filter has pore sizes between 0.1 microns and 0.4 microns.

Variation 30″. The injector device of variation 28″, wherein thesterilizing filter comprises a low-protein binding filter membrane.

Variation 31″. The injector device of variation 28″, wherein thesterilizing filter is located within the luer connector.

Variation 32″. A system for delivering a pharmaceutical formulation intothe eye comprising: the injector device of variation 1″; and a drugreservoir.

Variation 33″. The system of variation 32″, wherein the drug reservoircomprises an active agent.

Variation 34″. The system of variation 33″, wherein the active agentcomprises an anti-VEGF agent selected from the group consisting ofranibizumab, bevacizumab, aflibercept, and modifications, derivatives,and analogs thereof, and combinations thereof.

Variation 35″. The system of variation 33″, wherein the active agentcomprises ranibizumab or bevacizumab.

Variation 36″. The system of variation 33″, wherein the active agentcomprises aflibercept, ocriplasmin, a steroid, a placenta-derived growthfactor, a platelet-derived growth factor, or combinations thereof.

Variation 37″. The system of variation 33″, wherein the active agentcomprises an anti-complement agent, an anti-complement fraction agent, acomplement-blocking agent, a complement-enhancing agent, a classiccomplement pathway inhibiting agent, an alternative complementinhibiting agent, a classic complement pathway potentiating agent, analternative complement potentiating agent, or a combination thereof.

Variation 38″. A method for injecting a pharmaceutical formulation intothe eye comprising: coupling an injector attachment to an injectordevice having a proximal end and a distal end, the injector attachmentcomprising a needle assembly having a drug conduit, a priming-enablingcomponent, and a resistance component; priming the drug conduit usingthe priming-enabling component; generating a resistive force with theresistance component; advancing the drug conduit through the eye wall;and injecting the pharmaceutical formulation into the eye.

Variation 39″. The method of variation 38″, wherein the resistive forceis between 0 N and about 2 N.

Variation 40″. The method of variation 40″, wherein the resistive forceis between about 0.05 N and about 0.5 N.

Variation 41″. The method of variation 38″, wherein the resistancecomponent comprises a slidable sleeve.

Variation 42″. The method of variation 38″, wherein the resistancecomponent comprises a lever having a locked configuration and anunlocked configuration.

Variation 43″. The method of variation 42″, wherein depression of oneside the lever places the lever in its unlocked configuration.

Variation 44″. The method of variation 38″, wherein the pharmaceuticalformulation is preloaded in the syringe.

Variation 45″. The method of variation 38″, wherein the pharmaceuticalformulation is loaded into the syringe immediately prior to its use.

Variation 46″. The method of variation 38″, wherein the pharmaceuticalformulation comprises an active agent.

Variation 47″. The method of variation 46″, wherein the active agentcomprises an anti-VEGF agent selected from the group consisting ofranibizumab, bevacizumab, aflibercept, and modifications, derivatives,and analogs thereof, and combinations thereof.

Variation 48″. The method of variation 46″, wherein the active agentcomprises ranibizumab or bevacizumab.

Variation 49″. The method of variation 46″, wherein the active agentcomprises aflibercept, ocriplasmin, a steroid, a placenta-derived growthfactor, a platelet-derived growth factor, or combinations thereof.

Variation 50″. The method of variation 46″, wherein the active agentcomprises an anti-complement agent, an anti-complement fraction agent, acomplement-blocking agent, complement-enhancing agent, a classiccomplement pathway inhibiting agent, an alternative complementinhibiting agent, a classic complement pathway potentiating agent, analternative complement potentiating agent, or a combination thereof.

IV. Examples

The following examples serve to more fully describe the manner of usingthe above-described intraocular injection devices. It is understood thatthis example in no way serves to limit the scope of the invention, butrather is presented for illustrative purposes.

Example 1 Resistance Force Generated By the Slidable Sleeve/Shield

An intraocular injection device comprising a 30-gauge needle covered bya dynamic sleeve was fixed onto an Imada tensile testing bed and movedagainst an Imada 10 N force gauge at a rate of 10 mm/minute. Theresistance force was measured while the sleeve was pushed back to exposethe needle simulating the movement of the sleeve in practice. Thisproduced a “U”-shaped force plotted against the sleeve displacementcurve, as shown in FIG. 46. The resistance force at the beginning andthe end of sleeve movement path was greater than that in the middle ofthe path. In FIG. 46, the illustrated range of resistance forcegenerated may be between zero Newton and about 2 Newton or between about0.01 Newton and about 1.0 Newton, or between about 0.05 Newton and about0.5 Newton.

In one instance, the resistance force at the beginning of the sleevepath equaled the force required for the 30- or 31-gauge needle topenetrate through the human sclera (e.g., between 0.2 Newton and 0.5Newton). When a using a higher-resistance sleeve was employed, theresistance force at the beginning of the sleeve path was greater thanthe force required for the 30- or 31-gauge needle to penetrate throughthe human sclera (e.g., over 1 Newton). However, the force was lowenough to be comfortable for the patient and avoid potential damage tothe eye (e.g., to avoid increase in intra-ocular pressure over 60 mmHg).In the middle portion of the sleeve movement path, the force approachedzero Newton.

Example 2 Needle Bend and Recovery Force

Tests were run to compare the needle bending and recovery forces of aneedle (labeled “Mini” in the graph shown in FIG. 64) having aneedle-stabilizing component (here a guide tunnel) to commerciallyavailable needles (Accu-needles and TSK needles; TSK Laboratory, Inc.,Japan).

A maximum of 30° deflection was set based on the length of the needles.Each type of needle was placed into fixture, and mill digital readoutswere zeroed and the balance was tared. The test needles were moved downagainst the deflection fixture and the force on the scale at each testinterval recorded until the maximum displacement was reached. The motionwas reversed on the mill and the recovery force at each interval wasrecorded. Any permanent deformation of the needle was recorded.

As shown in the graph, the “Mini” needles significantly increased thebending force required to bend or deform compared to the Accu-needlesand TSK needles. The 32 to 33 gauge “Mini” needles had a similarstiffness and resistance to bending as the commercially available 30gauge needles.

The invention claimed is:
 1. An injector device for drug deliverycomprising: a needle assembly, the needle assembly comprising: a needlehub comprising an input port on its proximal end for removableconnection to a distal end of a syringe comprising a drug reservoir; aneedle having a proximal portion, a distal portion, and an exit port onthe distal portion, the proximal portion of the needle housed within theneedle hub and a distal portion of the needle extending distally beyondthe needle hub; and a resistance component comprising a cylindrical,rigid slidable sleeve comprising a cavity within the slidable sleeve andconfigured for axial movement and configured such that the needle iscompletely circumscribed by the slidable sleeve when the slidable sleeveis in a first, distal position with respect to the needle hub, and thedistal portion of the needle extends distally beyond the slidable sleevewhen the slidable sleeve is in a second, proximal position with respectto the needle hub, wherein the slidable sleeve has a proximal end, adistal end, and a constant sidewall having a fixed axial length andconstant outer diameter when moved from the first position to the secondposition; and a priming-enabling component circumscribed by the slidablesleeve, the priming-enabling component located distal to the cavity andcomprising a needle tunnel configured such that the needle can axiallyslide with respect to the needle tunnel, the needle tunnel comprising afirst segment comprising a first diameter configured to prevent asolution from the drug reservoir from leaking from the exit port of thedistal portion of the needle back proximally into the cavity and asecond segment directly adjacent to and distal to the first segment, thesecond segment having a second diameter greater than that of the firstdiameter when: the distal end of the syringe is attached to the needleassembly, the needle assembly is primed such that the solution from thedrug reservoir flows through the needle and is expelled from the distalend of the needle, and the slidable sleeve is in the first, distalposition with respect to the needle hub.
 2. The injector device of claim1, wherein the input port comprises a luer connector.
 3. The injectordevice of claim 2, wherein the luer connector comprises an internal luerseal.
 4. The injector device of claim 3, wherein the internal luer sealcomprises a proximal extension of the needle and is configured to openinto the drug reservoir.
 5. The injector device of claim 1, wherein theneedle assembly further comprises a needle stabilization mechanism. 6.The injector device of claim 1, wherein the needle assembly comprisesone or more filters.
 7. The injector device of claim 1, wherein theneedle assembly comprises a hydrophilic filter.
 8. The injector deviceof claim 7, wherein the needle assembly further comprises a hydrophobicfilter.
 9. The injector device of claim 1, further comprising a needledeployment indicator.
 10. The injector device of claim 9, wherein theneedle deployment indicator comprises a high visibility dye.
 11. Theinjector device of claim 6, wherein the one or more filters comprises asterilizing filter.
 12. The injector device of claim 11, wherein thesterilizing filter has pore sizes between 0.1 microns and 0.4 microns.13. The injector device of claim 11, wherein the sterilizing filtercomprises a low protein binding filter membrane.
 14. The injector deviceof claim 13, wherein the sterilizing filter is located within the luerconnector.
 15. A system for delivering a pharmaceutical formulation intoan eye comprising: the injector device of claim 1; and the drugreservoir.
 16. The system of claim 15, wherein the drug reservoircomprises an active agent.
 17. The system of claim 16, wherein theactive agent comprises an anti-VEGF agent selected from the groupconsisting of ranibizumab, bevacizumab, aflibercept, and modifications,derivatives, and analogs thereof, and combinations thereof.
 18. Thesystem of claim 16, wherein the active agent comprises ranibizumab orbevacizumab.
 19. The system of claim 16, wherein the active agentcomprises aflibercept, ocriplasmin, a steroid, a placenta-derived growthfactor, a platelet-derived growth factor, or combinations thereof. 20.The system of claim 16, wherein the active agent comprises ananti-complement agent, an anti-complement fraction agent, acomplement-blocking agent, a complement-enhancing agent, a classiccomplement pathway inhibiting agent, an alternative complementinhibiting agent, a classic complement pathway potentiating agent, analternative complement potentiating agent, or a combination thereof. 21.The injector device of claim 1, wherein the at least two segments of thepriming-enabling component comprises a proximal segment with a narrowerinternal diameter and a distal segment with a wider internal diameter.22. The injector device of claim 1, wherein the needle tunnel expands atits distal end to form a funnel or conical shape.
 23. The injectordevice of claim 1, wherein the proximal segment of the at least twosegments has a diameter that is the same as that of an outer diameter ofthe needle.
 24. The injector device of claim 1, wherein the proximalsegment of the at least two segments has a diameter that is within+/−0.12 mm of an outer diameter of the needle.